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Lunenfeld Prelims.qxd 8/23/2007 5:46 PM Page i

Textbook of Men’s
Health and Aging
2nd Edition
Lunenfeld Prelims.qxd 8/23/2007 5:46 PM Page ii
Lunenfeld Prelims.qxd 8/23/2007 5:46 PM Page iii

Textbook of Men’s
Health and Aging
2nd Edition

Editors in Chief

Bruno Lunenfeld MD FRCOG FACOG [Hon]

Professor Emeritus, Reproductive Endocrinology,
Bar-Ilan University, Ramat Gan
Israel

Louis JG Gooren MD
Professor, Vrjie Universiteit Medical Center,
Amsterdam, The Netherlands

Alvaro Morales MD
Queen’s University General Hospital,
Kingston, Ontario, Canada

John E Morley MB MCh

St Louis University,
St Louis, MO, USA
Lunenfeld Prelims.qxd 8/23/2007 5:46 PM Page iv

© 2007 Informa UK Ltd

First published in the United Kingdom in 2007 by Informa Healthcare, Telephone House, 69-77 Paul Street, London EC2A 4LQ.
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Lunenfeld Prelims.qxd 8/23/2007 5:46 PM Page v

Foreword

This a long road knows no turning (Sophokles: Ajax) to meet one of the greatest challenges of the 21st
century, which will profoundly affect many aspects
In the “sleepwalkers” (1964) Arthur Koestler of our life, social institutions and perhaps even eth-
remarks that “I mistrust the word progress and much ical values. The Population division of the United
prefer the word evolution simply because progress, Nations Secretariat estimates that last year (2006)
by definition, can never go wrong, whereas evolu- some 11% of the global population (688 million
tion constantly does and so does the evolution of persons) were aged 60 years or more and 13% of
the ideas. Indeed, it is fascinating to observe these persons were aged 80 years and over. The sex
throughout history the evolution of quite a few “rul- ratio of those aged 60 and over was 82 men for 100
ing” ideas , moving from gradual acceptance, to women and among those aged 80 years and more it
popularization, vulgarization, overextension, col- was 55 men for 100 women. Life expectancy at the
lapse and disappearance. At the height of their age of 60 was 17 years for men and 21 years for
importance, some of them are so generally accepted, women. The Population division projects that by
that they become the spirit of the time (the famous the year 2050 , 22% of the world population (or
“Zeitgeist” in German) with all of its societal conse- almost 2 billion people) will be aged 60 years and
quences, masterfully characterized by Virginia over and that 20% of these 2 billion persons will be
Woolf (1929) saying that “what is amusing now had aged 80 years or more. The United Nations also
to be taken in desperate earnest once”. Other ideas point out that, by the year 2050 – for the first time
may show a markedly different evolution; as Jean in our history – the population of persons older than
Monnet (1978) emphasized in his Mémoires, “When 60 years will be larger than the population of chil-
an idea corresponds to the necessity of an epoch , it dren (0 to 14 years of age). Humankind is growing
ceases to belong to those who invented it and it rapidly and it is ageing very rapidly… Fortunately,
becomes stronger than those who are in charge of scientific knowledge is growing even more rapidly .
it”. In fact, such an idea may become stronger than In 1830, Alfred Tennyson still could say with some
political power by developing into the common justification that “Science moves, but slowly slowly,
property of humankind ; it may deeply influence the creeping on from point to point ”. However, by the
spiritual content of an entire era and may resist the mid-fiftees of the 20th century it was recognized,
historical forces of destruction for a long time. In a that science progresses in proportion to the mass of
few, rare , cases a new idea becomes exceptionally knowledge that is left to it by preceding generations,
strong, when – in addition – it is generated as a that is under the most ordinary circumstances in
response to powerful historical challenges by some geometrical proportion (F.Engels, 1963). The same
new realities. The ageing of populations presents year Derek John de Solla Price has put this progress
such a challenge. It is a fundamentally new and in a proper perspective: “Using any reasonable defi-
unique problem in our history, with no previous nition of a scientist, we can say that between 80 and
analogies. Hence, people and their governments 90 per cent of all scientists that have ever lived are
have not had yet enough time (and/or courage?) to alive now. Now depending on what one measures
consider the necessary - and in part fundamental – and how, the crude size of science in manpower or
socioeconomical and political adjustments needed in publications tends to double within a period of
Lunenfeld Prelims.qxd 8/23/2007 5:46 PM Page vi

Foreword

10 to 15 years”. This was 44 years ago and nowadays contemporary knowledge, particularly, when it
it is often said that today the amount of new infor- contains so many carefully selected articles, as the
mation tends to double every 6 to 7 years…. And present textbook. In fact, when the perimeter
when the amount of new information increases so between the known and unknown rapidly increases,
rapidly, the perimeter between the known and it inevitably results in increasing specialisation and
unknown also increases and opens new avenues in the establishment of new disciplines. The estab-
for fruitful investigation. If I am allowed to quote lishment of a new discipline for the Study of the
another forword written more than 400 years ago, in Ageing Male slightly more than a decade ago, was
the Preface to De La Sagesse, Pierre Charron considered then by some medical scientists as a
remarks that “La vraye science et le vray étude de courageous innovation with a somewhat uncertain
l´homme c´est l´homme” (The true science and study future. Few, if any of them would doubt today that
of mankind is this discipline has come to stay and for a long time,
man). This will particularly be true in the world of since more and more evidence is forthcoming to
tomorrow, where the octagenarian populations will indicate that many aspects of ageing are gender spe-
grow most rapidly of all groups and lot of new infor- cific, like the localisation of certain receptors in dif-
mation will be required on their pathophysiology ferent tissues or the functions of the blood-brain
and optimal medical care.It is said, that Leonardo barrier. Therefore, an in-depth study of the various
da Vinci was the last scientist in history, who still aspects of gender specificity is likely to lead to
could grasp the entire body of knowledge of his improved diagnostic and therapeutic methods for
epoch. I doubt very much that there exists any med- ageing populations. Therefore, as Shakespeare says
ical scientist today, who could claim to grasp all “What is past is prologue”. Last, but not least, I feel
medical knowledge, or eventhat of any major disci- that the scientific community ought to be grateful
pline, the Study of the Ageing Male being no to theeditors and contributors of this Textbook.
exception. It is sufficient to look at a few of the Their effort should remind us that the acquisition,
almost 60 excellent articles of the present textbook critical evaluation, systematisation and dissemina-
to be convinced. Science is organized knowledge, said tion of positive knowledge are the only human
Herbert Spencer; therefore, a textbook will always activities which are truly cumulative and progres-
represent an important contribution to the body of sive (George Sarton, 1930, paraphrased).

vi
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Preface & Acknowledgments

Text to come
Lunenfeld Prelims.qxd 8/23/2007 5:46 PM Page viii
Lunenfeld Prelims.qxd 8/23/2007 5:46 PM Page ix

Contents

Introduction 1
History of research on the aging male – selected aspects 1
Micheal Oettel, Sergio Musitelli & Dirk Schultheiss

Section I: Biology of aging 11

1. The biology of gender differences in animal models of aging 13
HJ Armbrecht
2. The biologic basis for longevity differences between men & women 23
Rafi T Kevorkian & Oscar A Cepeda
3. The biology of the aging brain 31
Xi Chen & Shirley Shidu Yan
4. The blood-brain barrier: age & gender differences 39
William A Banks

Section II: Diagnostics & Primary Assessment 47

5. Aging men – The challenge ahead 49
Bruno Lunenfeld
6. Screening of the aging male 63
Louis JG Gooren, Alvaro Morales & Bruno Lunenfeld
7. Laboratory tests in the endocrine evaluation of aging males 97
Michael John Wheeler

Section III: The Genitourinary System 111

8. Genitourinary System: an introduction 113
Claude C. Schulman
9. Benign prostatic hyperplasia 115
Simon RJ Bott & Roger S Kirby
10. Prostate cancer 131
Michaël Peyromaure, Vincent Ravery & Laurent Boccon-Gibod
11. Erectile dysfunction in the aging male 147
Andrea Gallina, Alberto Briganti, Andrea Salonia, Federico Dehò,
Giuseppe Zanni, Pierre I Karahiewiz & Francesco Montorsi
12. Infertility in the aging male 161
Wolfgang Weidner, Thorsten Diemer & Martin Bergmann
13. Urinary incontinence 167
Adrian Wagg
14. Testicular cancer 183
Axel Heidenreich
Lunenfeld Prelims.qxd 8/23/2007 5:46 PM Page x

Contents

Section IV: Sexual Dysfunction 205

15. Treatment of erectile dysfunction in the elderly 207
Kok Bin Lim & Gerald B Brock
16. Assessment of the aging man with sexual dysfunction 229
Sidney Glina

Section V: Endocrine System 239

17. Endocrinology of the aging male: an overview 241
John E Morley
18. Androgen deficiency and its management in elderly men 245
Louis JG Gooren & Bruno Lunenfeld
19. Growth hormone and aging in men 265
Marc R Blackman
20. The Thyroid 273
Mary H Samuels & Jerome M Hershman

Section VI: Aging and Body Composition 281

21. Aging testosterone, and body composition 283
Alex Vermeulen
22. Growth hormone & body composition in the aging male 289
Fred Sattler
23. Androgens & lean body mass in the aging male 307
Melinda Sheffield-Moore, Shanon Casperson & Randall J Urban
24. Visceral obesity, androgens and the risks of cardiovascular disease 313
Louis JG Gooren

Section VII: Nutrition, Digestion and Metabolism 327

25. Nutrition in older men 329
David R Thomas
26. Obesity in middle-aged men 345
Richard YT Chen & Gary A Wittert
27. Diabetes in the elderly male: nutritional aspects 355
John E Morley
28. Lipids through the ages 363
Margaret-Mary G Wilson
29. Insulin resistance syndrome in older people 373
Angela Marie Abbatecola & Giuseppe Paolisso
30. Free radicals and vitamins 391
Seema Joshi
31. Resistance exercise 405
Charles P Lambert
32. Constipation & diarrhoea 421
Syed H Tariq
33. Macrovascular complications in the elderly diabetic 431
Nikiforos Ballian, Mahmoud Malas, and Dariush Elahi
34. Upper gastrointestinal complaints 443
Christopher K Rayner & Michael Horowitz

x
Lunenfeld Prelims.qxd 8/23/2007 5:46 PM Page xi

Contents

Section VIII: Cardiovascular and Respiratory System 463

35. Atherosclerotic risk assessment of androgen therapy in aging men 465
David Crook
36. Male aging: changes in metabolic, inflammatory, and endothelial
indices of cardiovascular risk 473
Ian F Godsland
37. Androgens: Studies in animal models of atherosclerosis 487
Peter Alexandersen
38. Androgens and blood pressure in men 501
Guy Lloyd
39. Androgens and arterial disease 511
Carolyn M Webb & Peter Collins
40. Androgenic influences on ventilation and ventilatory responses to
oxygen and carbon dioxide during wakefulness and sleep 517
Christopher P Cardozo
41. The role of androgens in respiratory function 521
Ann M Spungen

Section IX: Central Nervous System and Psyche 529

42. Changes in libido/sex life 531
Syed H Tariq
43. Depression 539
Margaret-Mary G Wilson
44. Testosterone, depression and cognitive function 551
John E Morley
45. Modern antidepressants 561
Margaret-Mary G Wilson
46. Sleep disorders 575
Hosam K Kamel
47. Cognitive changes in aging 683
Syed H Tariq & John E Morley

Section X: Skeletal System 609

48. Bone loss and osteoporotic fracture occurrence in aging men 611
Steven Boonen & Dirk Vanderschueren

Section XI: Sensory Organs 619

49. Aging and the eye 621
Ali R Djalilian & Hamid R Djalilian
50. Aging and inner ear dysfunction 631
Emiro Caicedo, Diego Preciado, George Harris & Frank Ondrey
51. Smell and taste 645
Weiru Shao & Frank Ondrey

Section XII: Skin and Hair 659

52. Healthy skin aging 661
Walter Krause

xi
Lunenfeld Prelims.qxd 8/23/2007 5:46 PM Page xii

Contents

53. Skin disease caused by changes in the immune system and infection 677
Isaak Effendy and Karen Kuschela
54. Skin changes caused by venous diseases 691
Eberhard Rabe & F Pannier
55. Aging of Hair 697
Ralph Trüeb & Rolf Hoffmann

Epilogue 709
56. Hormone treatment and preventative strategies in aging men:
whom to treat, when to treat and how to treat 711
Louis JG Gooren, Alvaro Morales & Bruno Lunenfeld

Index 731

xii
Lunenfeld Prelims.qxd 8/23/2007 5:46 PM Page xiii

Contributors

Angela Marie Abbatecola Marc R Blackman, MD

Department of Geriatric Medicine National Center for Complementary &
and Metabolic Diseases Alternative Medicine
Il University of Naples National Institutes of Health
Italy Bethesda, MD
USA
Peter Alexandersen, MD
Center for Clinical & Basic Research Laurent Boccon-Gibod, MD PhD
Vejle, Denmark Professor
CHU BICHAT
HJ Armbrecht PhD University of Paris VII, Paris
Professor of Biochemistry & France
Molecular Biology
Geriatric Research, Education & Steven Boonen, MD PhD
Clinical Center Leuven University Center for Metabolic Bone Diseases
St. Louis VA Medical Center Katholieke Universiteit Leuven
St. Louis, MO, USA & Belgium
St. Louis University
School of Medicine, MO Simon RJ Bott, FRCS
USA Trustees of the London Clinic Ltd
London
Nikiforos Ballian
UK
Johns Hopkins University
School of Medicine
Alberto Briganti
USA
Department of Urology
William A Banks, MD Vita-Salute University
GRECC, VA Medical Center Milan
St. Louis & Division of Geriatric, Italy
Department of Internal Medicine
St. Louis University School of Medicine, MO Gerald B Brock MD FRCSC
USA St. Joseph's Health Centre
London
Martin Bergmann Canada
Institut fur Veterinär-Anatomie
Histologie und Embryologie Emiro Caicedo, MD
der Justus-Liebig-Universität Giessen University of Minnesota
Germany Minneapolis, MN
USA
Lunenfeld Prelims.qxd 8/23/2007 5:46 PM Page xiv

Contributors

Christopher P Cardozo MD Thorsten Diemer

VA Medical Center Poliklnik für Urologie und Kinderurologie
Bronx, NY, USA and Zentrum für Chirurgie, Anästhesiologie
Associate Professor of Medicine und Urologie, Universitätsklinikum
Mount Sinai School of Medicine Giessen und Marburg GmbH
New York, NY Standort Giessen
USA Justus-Liebig-Universität Giessen
Germany
Shanon Casperson, DTR
Ali R Djalilian, MD
Oscar A Cepeda, MD National Eye & Health Institute
Fellow, Division of Geriatric Medicine Bethesda, MD
Department of Internal Medicine USA
St. Louis University School
of Medicine & GRECC VA Medical Center Hamid R Djalilian, MD
St. Louis, MO UCI Medical Center
USA University of California
Irvine, CA, USA
Richard YT Chen
Associate Consultant (Endocrinology) Isaak Effendy MD
Department of Medicine Department of Dermatology
Changi General Hospital Municipal Hospital of Bielefeld
Singapore Germany

Xi Chen, MD PhD Dariush Elahi, MD

Department of Neurology Johns Hopkins University
St. Louis University School of Medicine & School of Medicine
St Louis VA Medical Center, MO USA
USA
Andrea Gallina
Peter Collins MD FRCP FESC Department of Urology
National Heart & Lung Institute Vita-Salute University
London Milan
UK Italy

David Crook, PhD Spas V Getov

St. Bartholomew’s & Royal London School of Medicine Academic F2 SHO in Stroke Medicine
London Brighton and Sussex University Hospitals
UK UK

Federico Dehò Sidney Glina, MD PhD

Department of Urology Head of Department of Urology
Vita-Salute University Hospital Ipiranga, and Director of Instituto H Ellis
Milan São Paulo
Italy Brazil

xiv
Lunenfeld Prelims.qxd 8/23/2007 5:46 PM Page xv

Contributors

Ian F Godsland, PhD Rafi T Kevorkian, MD

Faculty of Medicine Assistant Professor
Imperial College London Division of Geriatic Medicine,
St Mary’s Hospital Department of Internal Medicine
London St. Louis University School of Medicine &
UK GRECC VA Medical Center
St. Louis, MO
George Harris, BS
USA
Axel Heidenreich, MD
Klinikum der Philipps- Roger S Kirby MA MD FRCS (UROL) FEBU
Universitat Marburg Professor, the Prostate Centre
Germany London
UK
Jerome M Hershman, MD
West Los Angeles VA Medical Center Walter Krause, MD
Los Angeles, CA Philipps University Marburg
USA Medical Center
Marburg
Rolf Hoffmann, MD Germany
Dermaticum
Freiburg Karen Kuschela
Germany Department of Dermatology
Municipal Hospital of Biekfeld
Michael Horowitz Biekfeld
University of Adelaide Germany
Department of Medicine
Royal Adelaide Hospital Charles P Lambert PhD
Australia Assistant Professor
University of Arkansas for
Seema Joshi, MD Medical Sciences
St. Louis University Medical Center Little Rock, AR
St. Louis, MO USA
USA
Richard W Lee
Hosam K Kamel MD MPH Academic F2 SHO in Stroke Medicine
Director, Geriatrics & Brighton and Sussex University
Extended Care Hospitals
St. Joseph’s Mercy Health Center UK
Hot Springs National Park, Arkansas
USA Kok Bin Lim
Singapore General Hospital
Pierre I Karakiewiz Singapore
Cancer Prognostics &
Health Outcomes Unit Guy Lloyd, MD FRCP
University of Montreal, Quebec East Sussex NHS Trust
Canada UK

xv
Lunenfeld Prelims.qxd 8/23/2007 5:46 PM Page xvi

Contributors

Mahmoud Malas Diego Preciado, MD PhD

Johns Hopkins University Assistant Professor
School of Medicine George Washington University School of Medicine
USA Children's National Medical Center, DC
USA
Francesco Montorsi, MD
Professor Eberhard Rabe
Department of Urology Professor of Dermatology
Vita-Salute University Klinik und Poliklinik für Dermatologie
Milan, Italy University of Bonn
Germany
John E Morley MB BCH
Divison of Geriatric Medicine C Rajkumar
St Louis University School of Medicine, Chair in Geriatrics and Stroke Medicine
MO, USA and VA GRECC Brighton and Sussex Medical School
Medical Center, St Louis, MO UK
USA
Vincent Ravery, MD PhD

Sergio Musitelli Professor

Hospital Bicat
Michael Oettel Paris, France

Frank Ondrey MD PhD Christopher K Rayner

University of Minnesota School of Medicine University of Adelaide
Minneapolis, MN Department of Medicine
USA Royal Adelaide Hospital
Australia
Feliztas Pannier
Dermatology Clinic and Polyclinic Andrea Salonia, MD
Rheinischen Friedrich Wilhelms Department of Urology
Universitat Vita-Salute University
Bonn Milan, Italy
Germany
Mary H Samuels, MD
Giuseppe Paolisso, MD Oregon Health and Science University
Department of Geriatric Medicine and Portland, Oregon
Metabolic Diseases USA
Il University of Naples
Italy Fred Sattler, MD
Professor of Medicine & Biokinesiology
Michaël Peyromaure, MD Keck School of Medicine
Service d'Urologie University of Southern California
Hospital Cochin Los Angeles, CA
Paris USA
France

xvi
Lunenfeld Prelims.qxd 8/23/2007 5:46 PM Page xvii

Contributors

Claude C. Schulman, MD Ralph Trüeb, MD

University Clinics Brussels Department of Dermatology
Belgium University of Zurich
Switzerland
Weiru Shao, MD
Director, Division of Otology & Neurotology Randall J Urban, MD
Tufts- New England Medical Center Professor
Boston, MA University of Texas Medical Branch
USA Galveston, TX
USA
Melinda Sheffield-Moore, PhD
Associate Professor Dirk Vanderschueren, MD PhD
University of Texas Medical Branch Katholieke Universiteit Leuven
Galveston, TX Belgium
USA
Alex Vermeulen, MD
Shirley Shidu Yan, MD
Professor Emeritus
Department of Pathology
University Hospital Ghent
College of Physicians & Surgeons
Belgium
Columbia University
New York Adrian Wagg, FRCP
USA Senior Lecturer in Geriatric Medicine
Ann M Spungen, PhD University College London Hospital
Associate Professor of Medicine UK
and Rehabilitation Medicine
Carolyn M Webb PhD
Mount Sihai School of Medicine
New York, NY, USA, and
Wolfgang Weidner, MD
Co-chair VA cooperative Study
Direktor der Klinik und Poliklnik
VA Medical Center
für Urologie und Kinderurologie
Brunx, NY
Zentrum für Chirurgie
USA
Anästhesiologie und Urologie
Syed H Tariq, MD FACP Universitätsklinikum Giessen und
Assistant Professor of Medicine Marburg GmbH
Division of Geriatic Medicine Standort Giessen
St. Louis University Medical Center Justus-Liebig-Universität Giessen
St Louis, MO, USA & GRECC Veterans Affairs Germany
Medical Center
St. Louis, MO Michael John Wheeler
USA Professor
Department of Chemical Pathology
David R Thomas, MD FACP AGSF Guy’s & St. Thomas Foundation Trust
Division of Geriatric Medicine St. Thomas Hospital
St. Louis University Health Sciences Center London
St. Louis, MO UK
USA

xvii
Lunenfeld Prelims.qxd 8/23/2007 5:46 PM Page xviii

Contributors

Margaret-Mary G Wilson, MD MRCP Giuseppe Zanni

Division of Geriatric Medicine Department of Urology
St. Louis University Vita-Salute University
St. Louis, MO Milan
USA Italy

Gary A Wittert
Mortlock Professor of Medicine and Head
Department of Medicine
University of Adelaide
Royal Adelaide Hospital
Australia

xviii
Lunenfeld Introduction.qxd 8/23/2007 4:48 PM Page 1

INTRODUCTION

History of research on the

aging male – selected aspects
Michael Oettel, Sergio Musitelli, and Dirk Schultheiss

Doubtless, in all periods of the history of mankind Here we can discuss and reflect only selected
the possibility of prolonging the life of the man historic aspects pronouncing the endocrinologic back-
including the preservation of his masculinity has ground of hypogonadism and testosterone therapy. For
claimed more attention than the treatment and/or more historic details, see references 1 to 14.
cure of, e.g., specific infectious, cardiovascular, Obviously, the highly sophisticated molecular
mental, or tumor diseases. This interest was also pharmacology of androgen action substantially
often greater than the impetus to find new ways for improved our knowledge of the molecular biology of
the treatment of women’s diseases – at least in patri- endogenous signal systems in the second half of the
archal periods. In early primitive civilizations, last century. Nevertheless, there is still a certain sus-
erotic matters including those of aging males were picion in some quarters about androgen therapy.
of prime importance and became an integral part of Why should that be so? A look at the history of
life. According to Hippocrates, old men suffer from testosterone therapy in aging men shows remark-
difficulty in breathing, catarrh accompanied by able scientific achievements, but often, however,
coughing, strangury, difficult micturition, pains at also a great deal of speculation and many dubious
the joints, kidney diseases, dizziness, apoplexy, practices. Already John Hunter (1728–1793) per-
cachexia, pruritus of the whole body, sleeplessness, formed testicular transplantation experiments while
watery discharges from the bowels, eyes and nostrils, studying tissue transplantation techniques in 1767
dullness of sight, cataract, and hardness of hearing.1 and, almost a century later, Arnold Berthold
The history of research on elderly men’s health (1801–1863) linked the physiologic and behavioral
reflects most parts of the broad cultural history and, changes of castration to a substance secreted by
therefore, an attempt to press this field into only the testes. He wrote in 184915 ‘Da nun aber an
one chapter of a textbook is at the beginning an act fremden Stellen transplantierte Hoden mit ihren
of despair. Additionally, the story of the ‘fountain of ursprünglichen Nerven nicht mehr in Verbindung
youth’ for males is also the story of wrong ways, stehen können, und da es, …, keine specifischen, der
blind alleys, hasty speculations, and of charla- Secretion vorstehenden Nerven giebt, so folgt, dass
tanism. Christian Wilhelm Hufeland (1762–1836) der fragliche Consensus durch das productive
characterized the unsuccessful attempts to prolong Verhältnis der Hoden, d.h. durch deren Einwirkung
life simply as ‘gerontokomic’. Furthermore, describ- auf das Blut, und dann durch entsprechende
ing our object in ancient times we are often unable Einwirkung des Blutes auf den allgemeinen
to distinguish between historic facts, mysticisms, Organismus überhaupt, …, bedingt wird.’ Summarizing
and mythologic or religious interpretations. transplanted testes affect behavioral and sexual

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characteristics by secreting a substance into the ‘To be able to contemplate with complacency
blood stream. either issue of a disorder which the great Author of
our being may, in his kindness, have intended as a
warning to us to prepare for a better existence, is of
Aging as an endocrine disorder? prodigious advantage to recovery, as well as to comfort,
and the retrospect of a well-spent life is a cordial of
The earliest contribution of modern medicine to infinitely more efficacy than all resources of the med-
the understanding of the clinical features of a disor- ical art.’ And this was just the opinion of the
der related to the beginning of aging was the article 90-year-old Cephalus at the very beginning of the
‘On the climacteric disease’ by Sir Henry Halford, dialogue ‘The Republic’ of Plato (428–348 BC).
which was read at the Royal College of Physicians For unknown reasons, the term climacteric was
in London in 1813:16 … ‘I will venture to question, not used again in relation to the aging male for
whether it be not, in truth, a disease rather than a more than 100 years, although the problem in gen-
mere declension of strength and decay of the nat- eral was discussed by other scientists, as demon-
ural powers.’ He seems to be the first to connect the strated, for example, in the studies of Charles
term climacteric with the symptoms observed in Edouard Brown-Séquard (see below). The French
some men between the ages of 50 and 75: physician Maurice de Fleury reactivated the topic in
‘Sometimes the disorder comes on so gradually and 1909 with his contribution ‘Sur le retour d’àge de
insensibly, that the patient is hardly aware of its l’homme,’ a condition detected in males ‘de quar-
commencement. He perceives that he is sooner ante et quelques années.’17 In addition to the clini-
tired than usual, and that he is thinner than he was; cal symptoms, he found significant changes in the
but yet he has nothing material to complain of. In genital organs of women. The thyroid gland was the
process of time his appetite becomes seriously main cause of the disease in men: ‘Pourtant, il est
impaired: his nights are sleepless, or if he gets sleep, une autre glande à secretion interne qui me paraît
he is not refreshed by it. His face becomes visibly jouer un role dans la genèse de ce faux retour d’àge:
extenuated, or perhaps acquires a bloated look. His je veux parler de la thyroid’.
tongue is white, and he suspects that he has fever.’ In July 1910, Archibald Church, professor of ner-
Halford pointed out that this disease had been over- vous and mental diseases in Chicago, Illinois, USA,
looked so far: ‘We find it generally complicated with published his article on ‘Nervous and mental distur-
other complaints, assuming their character, and bances of the male climacteric’, not citing any of the
accompanying them in their course, and perhaps above-mentioned works.18 On the other hand, he
this may be the reason why we do not find the cli- gave a detailed review of the literature dealing with
macteric disease described in books of nosology as a the issue of certain symptoms that might occur in a
distinct and particular distemper.’ Interestingly, ‘monthly rhythm in men’, e.g. variations in weight
concerning the etiology of this climacteric disease, and temperature, frequency of nocturnal emissions,
he drew no connection to the testes: ‘It is not very hemorrhoidal flux, or attacks of cardiac asthma. He
improbable that this important change in the con- even refers to the earlier ‘Selected papers on hysteria’
dition of the constitution is connected with a defi- of Sigmund Freud, who wrote ‘There are men who
ciency in the energy of the brain itself, and an show a climacterium like woman, and merge into an
irregular supply of the nervous influence to the anxiety neurosis at the time when their potency
heart.’ The therapeutic options were rather limited. diminishes.’ Church continues with his own descrip-
‘In fact, I have nothing to offer with confidence, in tion of symptoms observed over 10 years at the ‘invo-
that view, beyond a caution that the symptoms of lutional or climacteric period’ of his patients between
the disease be not met by too active a treatment.’ the ages of 50 and 65: ‘the particular interest of my
And, after suggesting ‘local evacuations’ and ‘warm subject does not pertain to the insanities, but to
purgatives’, Halford came to the conclusion: ‘For minor psychoses and neurotic disturbances. These,
the rest, “the patient must minister to himself ”.’ one and all, however, have mental background.’

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In October 1910, the German physician Kurt occurs in men. In this period, for example, poets,
Mendel19 and, in response to Mendel’s article, writers, and musicians have passed their zenith. Well
Bernard Hollander20 from England both published known exceptions are Joseph Haydn, who composed
articles entitled ‘Die Wechseljahre des Mannes the ‘The Creation’ with 66 and ‘The Seasons’ at 68
(Climacterium virile),’ claiming that they were also years of age, and Konrad Ferdinand Meyer and
aware of this clinical entity and had treated patients Theodor Fontane, who in their sixth and seventh
over the last decade. Mendel’s father, a well-known decades respectively reached the top of their artistic
university professor of neurology, had already used work. Hoche concluded that a true male climacteric
the term when dealing with such in his lectures. doesn’t exist, but men aged between 40 and 60 years
Although Mendel and Hollander approached the show many typical natural as well as pathologic
problem from the point of view of neurologists, they changes, which need mainly psychologic or psychi-
both agreed that the involution of the testes is the atric care. According to Diepgen (cited by Hoche23)
main pathomechanism responsible for the climac- the term ‘Wechseljahre’ (changing years for turn of
teric disease that can then be influenced by other life) is exemplified in German literature in the 17th
factors:19 ‘Sehe ich somit die Hypofunktion der and 18th centuries.
Keimdrüsen als Grundursache des beschriebenen August Werner from St Louis, USA, re-introduced
Krankheitsbildes an, so können daneben aber andere the term male climacteric (from the Greek for ‘rung
Momente in Betracht kommen, die als mitwirkende of a ladder’) in the late 1930s and today his name is
Faktoren bei Auslösung und Entwicklung des still associated with it by most authors. In 1939,
Leidens anzusprechen sind.’ Despite organotherapy Werner suggested the following theoretic back-
with ‘Spermin’ and unspecific treatments like cold ground for this clinical condition:24 ‘it seems reason-
showers and faradization of the body, Mendel sug- able to believe that many if not all men pass
gested psychotherapy as the preferable and most through a climacteric period somewhat similar to
successful therapeutic modality. Furthermore, he that of women, usually in a less severe but perhaps
discussed some forensic aspects of the climacteric in more prolonged form … . The endocrine dysfunc-
males. As is the case with women, a higher rate of tion, plus the imbalance of equilibrium between the
criminal acts – mainly consisting of insults towards two divisions of the autonomic nervous system,
others – is to be expected in the sixth decade of with evidence at times of disturbance in psychic
man’s life and this circumstance should be kept in centres, is the climacteric. The true climacteric is
mind by medical experts who are asked for their due primarily to decline of function of the sex
professional opinion in court. glands. Decline of sex function is not limited to
In 1916, the dermatologist and sexologist Max women but is also a heritage of all men.’25,26
Marcuse from Berlin drew a connection between
the ‘climacterium virile’ and some urosexual distur-
bances or changes of the prostate making his work Testosterone and the aging male
of special interest to urologists.21 In most of his
patients he detected an involuted small and soft Throughout history, many concepts have been sug-
prostate, a status he called ‘Prostata-Atonie’. In sev- gested and practiced to achieve eternal youth,
eral cases, he successfully applied either organother- longevity, and rejuvenation. To point out only one
apy with ‘Testikulin’, ‘Testogan’ and ‘Hormin’, or example, one might think of the biblical case
faradization of the prostate. (Kings, III, 1, 3 ff) of King David, who was old in
Two examples of comprehensive monographies years and showed a significant loss of ‘heat’.
on the topic written in German are ‘Über den Mann A young virgin was chosen to compensate this
von 50 Jahren’ by FK Wenckebach22 in 1915 and deficit: … ‘and let her lie in thy bosom, that my lord
‘Die Wechseljahre des Mannes’ by A Hoche23 in the king may get heat’. As the name of this virgin
1928. According to Hoche, in the sixth decade of was Abhisag the Sunamite, the method of bringing
life a deep decline in psychic and physical fitness an aged man in close contact with a young woman

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was, henceforth, called ‘sunamitism’ and this idea time:30 ‘Besides, it is well known that seminal losses,
was kept up among many others until recent cen- arising from any cause, produce a mental and phys-
turies and is still an attractive option of machismo ical debility which is in proportion to their fre-
for the future of mankind.27 quency. These facts and many others have led to the
Tales and myths about aphrodisiacs and rejuvena- generally admitted view that in the seminal fluid, as
tion extracts from testicular tissue or blood were secreted by the testicles, a substance or several sub-
reported from ancient times up to the present. As stances exist which, entering the blood by resorp-
early as 140 BC Suçruta of India advocated the tion, have a most essential use in giving strength to
ingestion of testis tissue for the cure of impotence. A the nervous system and to other parts.’ Arthur
vague foreshadow of the endocrine function of the Biedl,32 the author of the first textbook on internal
testis was speculated by Aretaeus of Cappadocia secretory organs in 1910 categorically states that:
(2nd to 3rd century AD) and more vigorously in ‘The date of birth of “the science of internal secre-
1775 by de Bordeu. They proposed that each organ tion” is that memorable meeting of the Société de
of the body produced a substance, which was Biologie of Paris of June 1st 1889, where Brown-
secreted into the blood to regulate bodily function.28 Séquard, then 72 years of age reported on his exper-
With the birth of modern endocrinology in the iments undertaken to prove his hypothesis by means
19th century, the testes and, later, their identified of subcutaneous injections of testicular juice into
hormonal product testosterone increasingly himself.’
attracted the interest of scientists who were investi- In 1902, Ancel and Bouin in France ligated the
gating the aging process. The first considerations ductus deferens in rabbits and noted atrophy of the
regarding the relationship between hormone pro- seminal epithelium. However, the Leydig cells
duction and the aging process stemmed from the remained unchanged, and many of the animals
French neurologist Charles Edouard Brown-Séquard appeared to have increased sexual activity.33 This
(1817–94), the son of a Philadelphia seaman, giving paved the way for Eugen Steinach (1861–1944) in
rise to the field of organotherapy. In 1869 he sug- Vienna. This physiologist started conducting experi-
gested injecting semen into the blood of old men in ments with testicular transplantation in animals at
order to increase mental and physical strength and the turn of the century in order to study the sexual
performed the first animal experiments 6 years later. differentiation and the hormonal function of the
His famous self-experiment at the age of 72 with gonads. In this theory of ‘autoplastic’ treatment of
several subcutaneous injections of a mixture of aging, he postulated an increased incretory hor-
blood from the testicular veins, semen, and juice monal production following the cessation of the
extracted from crushed testicles of young and vigor- secretory output of the gonads after surgical ligation
ous dogs and guinea pigs in 1889 was one of the first of the seminal ducts.34 The basic idea was that liga-
milestones for androgen therapy in the aging male. ture of the spermatic ducts leads to an atrophy of the
He reported an increase in his physical and mental seminal epithelium and (hopefully) to hypertrophy
abilities, a better stream of urine and the relief of of the Leydig cells. The first operation was per-
constipation. Brown-Séquard had inspired physi- formed in 1918 and resulted in a worldwide vasoli-
cians around the world to investigate the nature of gation boom over the next two decades. Steinach
this compound, and by the end 1889 over 12 000 nicely summarized the results of his scientific life in
physicians were administering this new ‘elixir of his late biography:35 ‘It has frequently been said that
life’.29 Nevertheless, Brown-Séquard’s ‘pharmaceu- a man is as old as his blood vessels. One may have
tic’ prescription must have been equivalent to a greater justification for saying that a man is as old as
placebo.27,30,31 The following passage on ‘seminal his endocrine glands.’
losses’, a condition Brown-Séquard also called ‘sper- Early in his career, the Russian Serge Voronoff
matic anemia’, and which was generally better (1866–1951), working in Paris and elsewhere, dis-
known as ‘spermatorrhoea’, reveals the limited cussed the life expectancy and signs of aging in
understanding of testicular endocrinology at that castrates. He was one of the first to transplant

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testicular tissue from a monkey into a human testi- pharmaceutic industry. Is it true, that they are
cle in 1920. He later became the world’s leading sur- all completely out of date now? Machluf and
geon to transplant testicular tissue from ape to co-workers42 reported on the microencapsulation of
man.36 But AS Parkes remembered as follows: ‘This Leydig cells as a system for testosterone supplemen-
attractive idea was naturally exploited in dubious tation in the future. And could stem cell technology
ways, and early in the period under review Voronoff, be the modern version of ‘organotherapy’ or ‘cellular
working in Algiers, became notorious for his so- therapy’?
called rejuvenation experiments on man and farm The identification and chemical synthesis of
animals. His claims were such that an international testosterone and other steroid hormones was
deputation visited his establishment in Algiers in achieved in the 1930s.43 This was a ‘condition sine
1927 to make a critical review of the work. The qua non’ for the further development of modern
report of the British contingent to the Ministry of endocrinology and the basis for a rational therapy
Agriculture was very cautious.’37 with sexual hormones. Only with the introduction
At the same time, several American surgeons per- of high-quality testosterone preparations did it
formed testicular transplantations (or rather: implan- become possible to provide a scientific basis for
tations), such as Victor D Lespinasse, Robert T androgen therapy.
Morris, Leo L Stanley, John R Brinkley, and George As defined traditionally, an androgen is a sub-
F Lydston.38 Victor Lespinasse, Professor of stance that stimulates the growth of the male repro-
Genitourinary Surgery at North-Western University, ductive tract. It is important to realize that this is a
treated impotence by oral glandular extracts. When biologic and not a chemical definition. Nonetheless,
this failed, Lespinasse grafted slices of human testi- the most potent androgens are steroids. It has been
cles taken from fresh cadavers into the rectus mus- proved to be a difficult challenge in steroid chem-
cle of impotent men. He believed that most cases istry to isolate, characterize, and synthesize the male
of impotence in middle-aged men were caused by hormones.44
a failure of hormone secretion, and reported posi- Pezard, in 1912, reported that aqueous extract of
tive results after several weeks, athough these were pig testes maintained the comb and wattles of the
transient.39 capon.28 18 years later, Gallagher and Koch devel-
Leo Stanley, a physician working at the San oped the response in the capon into a quantitative
Quentin Prison in California, performed 1000 tes- assay procedure, which was adopted with minor
ticular substance implantations into 656 prisoners modifications by most laboratories as the standard
under his care. Unlike Lespinasse, Stanley used the assay procedure for male hormone activity.45
testicles of goats, rams, boars, or deer. He cut the As early as 1927, Lemuel Clyde McGee46 demon-
testicles into strips of such a size that he could put strated the isolation of a biologically active extract
them into a pressure syringe for injection under the of the lipid fraction of bull testicles. In 1933
skin of the abdomen. He reported a marked McCullagh and co-workers47 reported in a very ele-
improvement in impotence.40 gant paper, using the chick comb assay for measuring
A rejuvenation boom took place in the early androgenic activity, that extracts from blood, urine, or
1920s with both vasoligation and testis implanta- spinal fluid of men are useful for the treatment of male
tion, which were performed by many doctors in hypogonadism. The authors called the substance
Europe and America.4,27 The Swiss genito-urinary which is produced in the testes ‘Androtin’. The mag-
surgeon Paul Niehans (1882–1971) claimed to have nitude of the problem faced by steroid chemists has
performed more than 50 000 ‘cellular therapy’ treat- been illustrated by the fact that labor-intensive
ments. He envisioned the replacement of organ extracts from up to 100 g of testes were required for a
transplantation by the injection of viable cells.4,41 positive result in the so-called chick comb bioassay.2,48
All these hormonal approaches to rejuvenation It is not surprising, therefore, that 15 mg of the first
were made before the discovery of testosterone or known androgen – androsterone – was isolated under
the supply of suitable androgen products by the the leadership of Adolf Butenandt, at the age of 28

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years, 15 000–25 000 liters of policemen’s urine in testosterone to men an effective natural form of
1931.49,50 The name of this relatively weak urinary treatment without serious side effects? This question
5α-reduced androgen comes from ‘andro’ = male, will be answered by some of the authors of this
‘ster’ = sterol, and ‘one’ = ketone. The chemical syn- textbook.
thesis of androsterone was performed by Leopold Heller and Myers57 demonstrated that climac-
Ruzicka and co-workers 3 years later.51 The Japanese teric symptoms of men could be reversed by testos-
workers Ogata and Hirano,52 not sufficiently terone propionate therapy. They utilized a quasi-
acknowledged by the Europeans and Americans, placebo trial to demonstrate this effect. Using the
found in 1934 that the androgen from the urine rat ovary-weight assay the authors demonstrated
(Butenandt’s androsterone) was not identical with elevated gonadotropin concentrations in the urine
the androgen extracted from boar testes. The andro- of climacteric men.
genic properties of this crystal hormone were more In 1946 Werner25 presented detailed results of the
active than any of the testicular preparations previ- evaluation of 273 climacteric male patients. The
ously reported. One year later, Karoly David, most prominent symptoms were nervousness,
Elizabeth Dingemanse, Janos Freud, and Ernst decreased potency, decreased libido, irritability,
Laqueur53 reported the isolation of testosterone, the fatigue, depression, memory problems, sleep distur-
main secretory product from the testes and the main bances, numbness, tingling, and hot flushes. Of these
androgen in the blood, from several tonnes of bull patients, 177 were treated with intramuscular testos-
testes. The term ‘testosterone’, coined by this Dutch terone propionate injections, only four of whom did
group, combines ‘testo’ = testes, ‘ster’ = sterol, and not benefit from the treatment. Werner’s summary is
‘one’ = ketone. In the same year, the chemical syn- convincing: ‘Men are subject to the hypogonadal or
thesis of testosterone was published by three groups climacteric syndrome, just are woman, when there is
from Germany, the Netherlands, and Switzerland, decrease of function or a function of the sexual
led by Adolf Butenandt,54 Ernst Laqueur,53 and glands. Testosterone propionate is as effective in
Leopold Ruzicka.55 Ruzicka and Butenandt were relieving the subjective symptoms of this syndrome
offered the 1939 Nobel Prize for chemistry for their in men as estrogen is in relieving the symptoms of
work, but Butenandt was forced by the Nazi govern- similar origin in women. Sex hormones should not be
ment to decline the honor. administered to men and women of climacteric age
Adolf Butenandt wrote in 1941:56 ‘Die heute syn- with the idea of stimulating increased sexual potency;
thetisch zubereiteten Hormone sind den natürlichen if this is the object of treatment, disappointment will
Wirkstoffen nicht nur ähnlich, sondern mit ihnen … result in the great majority of instances.’
identisch; sie stellen demnach keine Kunstprodukte One of the earliest long-term experiences with
dar im Sinne körperfremder Pharmaka mit hor- testosterone therapy came from the writer Ernest
monartiger Wirkung, sondern natürliche, kör- Hemingway. He took testosterone for the last decade
pereigene Wirkstoffe. Daher bedeutet die Behandlung of his life, providing us with one of the longest
eines Kranken mit den heute von der pharmazeutis- patient histories for testosterone administration.58
chen Industrie dargebotenen Hormonen eine In the first years after testosterone became avail-
Therapie auf natürlicher Basis.’ [The hormones syn- able, an overgenerous application of this new thera-
thesized today are not only similar to the naturally peutic option to the problem of the ‘climacteric in
occurring drug substances, but are identical with … the aging male’, was hinted at by an editorial in the
them; they are therefore not artificial products in the Journal of the American Medical Association in 1942:59
sense of exogenous pharmaceuticals with hormone- ‘Recently many reports have appeared in medical
like action, but rather natural, endogenous substances. journals claiming that a climacteric occurs in middle
Thus, the treatment of a patient with the hormones aged men. Brochures circulated by pharmaceutical
now offered by the pharmaceutical industry means manufacturers depict the woeful course of aging
a treatment on a natural basis.] Is this point of man. None too subtly these brochures recommend
view still applicable today? Is the administration of that male hormonal substance, like a veritable elixir

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or youth, may prevent or compensate for the other- It is also interesting to note, that the indications
wise inevitable decline. What of the postulated and contraindications for testosterone change with
occurrence of a climacteric in men?’. The answer time, and that in some cases the opinions of the old
came from the author in the same editorial: pioneers are reappearing in new clothes. For exam-
‘Androgens exert a tonic and stimulating action, ple, by 1937 testosterone therapy was being recom-
associated perhaps with their metabolic effects. Male mended for the treatment of benign prostatic
hormones provide replacement therapy in castrates hyperplasia (BPH)67 and was also state of the art in
but are also active in normal middle aged men beset the 1950s.68 Thereafter, BPH – at least in the
by aging processes which are in some large propor- obstructive stages – was to become one of the con-
tion irrespective of testicular function. Androgens traindications for androgens.69 Today, testosterone
may influence quite harmfully the physiologic and administration for BPH treatment is being revis-
psychologic condition of previously well adjusted ited.70 Also, it is well accepted that prostate cancer
elderly men, as has been observed incidental to the is an absolute contraindication for testosterone
trial use of male hormone substances in the treat- treatment.71 Nevertheless, recent papers show that
ment of benign hypertrophy of the prostate. Actual low levels of androgens in serum or prostate are cor-
evaluation of androgenic treatment cannot be related with higher prostate cancer aggressive-
avoided by glib explanation that men normally ness.72,73 Richmond Prehn speculated about the
undergo a spontaneous climacteric, an abruptly prevention and therapy of prostate cancer by andro-
occurring state of primary testicular insufficiency in gen administration.74 The treatment of erectile dys-
which male hormones act as substitutional therapy’. function (ED) by testosterone is another example.
The problem of hypogonadism of the aging man After initial euphoria in the middle of the last
starts with the definition. A lot of synonyms often century, testosterone administration later became a
represent a certain unsteadiness in the scientific malpractice. Now, the combination therapy of ED
community. At present, we have the following by PDE5 inhibitors together with testosterone is
synonyms: step by step and in some circumstances preferred.75

• changing years, or change of life, or (in German)

‘Wechseljahre’ Outlook
• andropause
• male climacteric or climacterium virile To summarize, the scientific work on aging and the
• androgen decline in aging males (ADAM) accompanying sexual and reproductive aspects
• partial androgen decline in aging males often led to breakthroughs in medicine, as can be
(PADAM) seen in original approaches in genetics, molecular
• acquired male hypogonadism biology, biochemistry, endocrinology, andrology,
• late onset hypogonadism. urology, pharmaceutic developments, and gerontol-
ogy as well as in geriatrics. Therefore the basic idea
For a critical statement about testosterone therapy of Vergil (70–19 BC), which was pronounced by the
see reference 60. The story of testosterone is unend- Russian writer Iwan S Turgenjew (1818–83) to be
ing. Astonishingly, the first paper describing the ‘finding the future by discovery of the past’76 can
conversion of testosterone to the powerful key also be used for research on the aging male.
metabolite 5α-dihydrotestosterone (DHT) in vitro However it is astonishing that research work on the
and in vivo was not submitted until 32 years after aging male from antiquity until the first half of the
the identification of testosterone.48 It was not until 20th century was for a long time more or less forgot-
two decades later that the groups led by Liao,61,62 ten, with the result that today the highlights from
Wilson,63,64 Brinkmann,65 and McPhaul,66 suc- the past pioneering age have to be defended in
ceeded in characterizing and expressing a cDNA comparison to modern ‘trendy’ approaches – and
encoding the human androgen receptor. unfortunately not vice versa!

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References 22. Wenckebach FK. Über den Mann von 50 Jahren.

Perles, Wien, 1915.
1. Musitelli S. The aging male in the literature. Aging 23. Hoche A. Die Wechseljahre des Mannes. Springer,
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2. Tausk M. The emergence of endocrinology. In: 24. Werner AA. The male climacteric. JAMA 1939;
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Pharmacology, Vol 2. Haemodynamics, Hormones 25. Werner AA. The male climacteric: report of two
and Inflammation. London: Elsevier Science hundred and seventy-three cases. JAMA 1946; 132:
Publishers, 1984: 219–49, 307–20. 188–94.
3. Kochakian CD. How it was. Anabolic action of 26. Morley JE, Perry HM. Androgen treatment of male
steroids and remembrances. The University of hypogonadism in older males. J Steroid Biochem Mol
Alabama School of Medicine, 1984. Biol 2003; 85: 367–73.
4. Schultheiss D, Denil J, Jonas U. Rejuvenation in the 27. Trimmer EJ. Rejuvenation: the history of an idea.
early 20th century. Andrologia 1997; 29: 351–5. Robert Hale, London, 1967.
5. Schultheiss D, Bloom DA, Wefer J, Jonas U. Tissue 28. Kochakian CD. History, chemistry and pharmacody-
engineering from Adam to the zygote: historical namics of anabolic-androgenic steroids. Wien Med
reflections. World J Urol 2000; 18: 84–90. Wschr 1993; Heft 14/15: 359–63.
6. Schultheiss D, Jonas U, Musitelli S. Some historical 29. Hansen B. New images of a new medicine: visual evi-
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Classical Writings on Erectile Dysfunction. An 30. Brown-Séquard CE. The effects produced on man by
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Millennia. Berlin: ABW Wissenschaftsverlag, 2005. testicles of animals. Lancet 1889; 137: 105–7.
8. Isidori A. Storia dell’andrologia moderna. Medicina 31. Cussons AJ, Bhagat CI, Fletcher SJ, Walsh JP.
nei secoli arte e scienza. 2001; 13: 255–68. Brown-Séquard revisited. A lesson from history on
9. Musitelli S, Gerokomikón. A brief survey of the his- the placebo effect of androgen treatment. Med J Aust
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Aging Male 2002; 5: 181–98. 32. Biedl A. Innere Sekretion. Urban und Schwarzenberg,
10. Musitelli S. The aging male in the Old Testament. Berlin, Wien, 1910.
Aging Male 2003; 6: 110–18. 33. Massaglia AC.The internal secretion of the testis.
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and death on Açvaghosa’s ‘Buddhacǎrǎta’ (The Feats 34. Steinach E. Verjüngung durch experimentelle
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sexuality in aging. Aging Male 2002; 5: 103–13. 36. Voronoff S. Testicular Grafting from Ape to Man.
14. Morley JE. A brief history of geriatrics. J Gerontology Brentanos, London, 1920.
2004; 59A: 1132–52. 37. Parkes AS. The rise of reproductive endocrinology
15. Berthold AA. Transplantation der Hoden. Arch 1926–1940. J Endocrinol 1965; 34: xx–xxxii.
Anat Physiol Wiss Med 1849; 16: 42–6. 38. Schultheiss D, Engel RM. G.Frank Lydston
16. Halford H. On the climacteric disease. Med Transact (1858–1923) revisited: androgen therapy by testicu-
1813; 4: 316–28. lar implantation in the early twentieth century. Worl
17. De Fleury. Sur le retour d’àge de l’homme. Bull Acad J Urol 2003; 21: 356–63.
Med Paris 1909; 62: 311–19. 39. Lespinasse VD. Transplantation of the testicle.
18. Church A. Nervous and mental disturbances of the JAMA 1913; 61: 1869–70.
male climacteric. JAMA 1910; 55: 301–3. 40. Stanley LL.An analysis of one thousand testicular
19. Mendel K. Die Wechseljahre des Mannes substance implantations. Endocrinology 1922; 6: 787.
(Climacterium virile). Neurol Zentralbl 1910; 29: 41. Freeman ER, Bloom DA, McGuire EJ. A brief history
1124–46. of testosterone. J Urol 2001; 165: 371–3.
20. Hollander B. Die Wechseljahre des Mannes 42. Machluf M, Orsola A, Boorjian S, Kershen R, Atala
(Climacterium virile). Neurol Zentralbl 1910; 29: 1282–6. A. Microencapsulation of Leydig cells: a system for
21. Marcuse M. Zur Kenntnis des Climacterium virile, testosterone supplementation. Endocrinology 2003;
insbesondere über urosexuelle Störungen und 144: 4975–9.
Veränderungen der Prostata bei ihm. Neurol 43. Hobermann JM, Yesalis CE. The history of synthetic
Zentralbl 1916; 35: 577–91. testosterone. Sci Am 1995; 272: 76–81.

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History of research on the aging male – selected aspects

44. Oettel M. The endocrine pharmacology of testosterone 62. Chang C, Kokontis J, Liao S. Molecular cloning of
therapy in men. Naturwissenschaften 2004; 91: 66–76. human and rat complementary DNA encoding
45. Gallagher TF, Koch FC.The quantitative assay for androgen receptors. Science 1988; 240: 324–6.
testicular hormone by comb growth reaction. 63. Lubahn DB, Joseph DR, Sar M, Tan J-A, Higgs HN,
J Pharmacol Exper Ther 1930; 40: 327–34. Larson RE, Frenach FS, Wilson EM. The human
46. McGee LC. The effect of an injection of a lipoid frac- androgen receptor: complementary deoxyribonucleic
tion of bull testicle in capons. Proc Inst Med Chicago acid cloning, sequence analysis and gene expression
1927; 6: 242–54. in prostate. Mol Endocrinol 1988; 2: 1265–75.
47. McCullagh EP, McCullagh DR, Hicken NF. 64. Lubahn DB, Joseph DR, Sullivan PM, Willard HF,
Diagnosis and treatment of hypogonadism in the French FS, Wilson EM. The human androgen receptor:
male. Endocrinology 1933; 17: 49–63. complementary deoxyribonucleic acid cloning,
48. Bruchovsky N, Wilson JD. The conversion of testos- sequence analysis and gene expression in prostate. Mol
terone to 5α-androstan-17β-ol,3-ome by rat prostate Endocrinol 1988; 2: 1265–75.
in vivo and in vitro. J Biol Chem 1968; 243: 1314–24. 65. Trapman J, Klaassen P, Kuiper GG, Korput JA van
49. Butenandt A. Über die chemische Untersuchung der der, Faber PW, Rooij HC van, Geurts van Kessel A,
Sexualhormone. Z Angew Chem 1931; 44: 905–8. Voorhorst MM, Mulder E, Brinkman AO. Cloning,
50. Butenandt A, Tscherning K. Über Androsteron. II. structure and expression of a cDNA encoding the
Seine chemische Charakterisierung. Z Angew Chem human androgen receptor. Biochem Biophys Res
1934; 229: 167–84. Commun 1988; 153: 241–8.
51. Ruzicka L, Goldberg MW, Meyer J, Brüngger H, 66. Tilley WD, Marcelli M, Wilson JD, McPhaul MJ.
Eichenberger E. Zur Kenntnis der Sexualhormone II. Characterization and expression of a cDNA encod-
Über die Synthese des Testikelhormons (Androsteron) ing the human androgen receptor. Proc Natl Acad
und Stereoisomere desselben durch Abbau hydrierter Sci USA 1989; 86: 327–31.
Sterine. Helv Chim Acta 1934; 17: 1395–406. 67. Laroche G, Marsan F, Bompard E, Corcos A.
52. Ogata A, Hirano S. Study on the male hormone L’hypertrophie de la prostate. Essais de traitement
(VI). Study on the male hormone from boar testes hormonal par les sels de testosterone. Presse Médicale
(III). A new crystal male hormone. J Pharm Soc Jpn 1937; 45: 932–6.
1934; 54: 199–211. 68. Banzer G. Arzneitherapie des praktischen Arztes,
53. David K, Dingemanse E, Freud J, Laqueur E. Über Dritte Auflage. Berlin and München: Urban &
kristallinisches männliches Hormon aus Hoden Schwarzenberg, 1949; 119.
(Testosteron), wirksamer als aus Harn und 69. Gooren L. Risks of androgen therapy. J Men’s Health
Cholesterin bereitetes Androsteron. Hoppe-Seylers Z Gender 2006; 3: 404–9.
Physiol Chem 1935; 233: 281–2. 70. Kaplan SA. Male pelvic health: a urological call for
54. Butenandt A, Hanisch G. Über Testosteron. arms. J Urol 2006; 176: 2351–2.
Umwandlung des Dehydro-Androsterons in 71. Qoubaitary A, Swerdloff RS, Wang C. Advances in
Androstendiol und Testosteron; ein Weg zur male hormone substitution therapy. Expert Opin
Darstellung des Testosterons aus Cholesterin. Hoppe Pharmacother 2005; 6: 1493–506.
Seyler’s Z Physiol Chem 1935; 237: 89–92. 72. San Francisco IF, Regan MM, DeWolf WC, Olumi
55. Ruzicka L, Wettstein A. Sexualhormone VII. Über AF. Low age adjusted free testosterone levels corre-
die künstliche Herstellung des Testikelhormons late with poorly differentiated prostate cancer. J Urol
Testosteron (Androsten-3-on-17-ol). Helv Chim 2006; 175: 1341–6.
Acta 1935; 18: 1264–75. 73. Nishiyama T, Ikarashi T, Hashimoto Y, Suzuki K,
56. Butenandt A. Aufgaben und Ziele der Takahashi K. Association between the dihydrotestos-
Hormonforschung. Pharmazeutische Industrie 1941; terone level in the prostate and prostate cancer
8: 43–5. aggressiveness using the Gleason score. J Urol 2006;
57. Heller CG, Myers GB. The male climacteric: its 176: 1387–91.
symptomatology. JAMA 1944; 126: 472–7. 74. Prehn RT. On the prevention and therapy of prostate
58. Morley JE, Perry HM. Andropause: an old concept in cancer by androgen administration. Cancer Res
new clothing. Clin Geriatr 2003; 19: 507–28. 1999; 59: 4161–4.
59. Editorial. Climacteric in aging men. JAMA 1942; 75. Yassin AA, Saad F, Diede HH. Testosterone and
118: 458–60. erectile function in hypogonadal men unresponsive
60. Handelsman DJ. Testosterone: use, misuse and abuse. to tadalafil: results from an open-label uncontrolled
Med J Aust 2006; 185: 436–9. study. Andrologia 2006; 38: 61–8.
61. Chang C, Kokontis J, Liao S. Structural analysis of 76. von Albrecht M. ‘Vergil’. Bucolica, Georgica,
complementary DANN and amino acid sequences of Aeneis. Eine Einführung. Universitätsverlag Carl
human and rat androgen receptors. Proc Natl Acad Winter, Heidelberg, 2006.
Sci USA 1988; 85: 7211–5.

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SECTION I

Biology of aging
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CHAPTER 1

The biology of gender differences in

animal models of aging
HJ Armbrecht

Introduction The biology of aging

One of the hallmarks of human aging is the gender What is aging?

difference. Across many different cultures and Miller has proposed a definition that captures the
genetic backgrounds, women on the average outlive basic elements of aging: ‘A process that converts
men by 7 years (see Chapter 2). Along with this, healthy adults into frail ones, with diminished
women seem more resistant to certain types of reserves in most physiological systems and an expo-
diseases than men. The fact that this gender differ- nentially increasing vulnerability to most diseases
ence is so robust would lead one to believe that it and to death.’2 Aging is not merely the passage of
has, at least in part, a biologic basis. Gender differ- time. It focuses on changes in adulthood rather than
ences are also seen in animal models of aging such on developmental changes, and it is characterized
as fruit flies, mice, and rats. The study of these by a decreasing ability to adapt to a changing envi-
animal models has shown that they mimic aspects ronment in a physiologic way. These changes may
of human aging in important ways. It is becoming involve nutrition, temperature, disease, and even
apparent that common biochemical pathways mod- societal changes. A hallmark of most aging organ-
ulate aging in these organisms and that these path- isms is an increase in the incidence of disease and
ways have their counterparts in humans.1 Thus, the the risk of death. This definition then makes the
study of gender differences in the aging of these distinction between the aging process and disease. It
organisms may give some insight into the marked assumes that there are fundamental aging processes
gender differences seen in human aging. that are not just the sum of all of the diseases of
This review is divided into four parts. First, we aging. These processes predispose the aging organ-
will discuss the aging process from a biologic per- ism to a greater likelihood of disease.
spective. Next, we will summarize the characteris-
tics of the aging process at the organs/systems level, Why do we age?
the cellular level, and the subcellular level. Then, The question of why we age can be approached
we will discuss gender differences in the aging of from many different perspectives – psychologically,
flies, mice, and rats. Finally, we will discuss the rel- sociologically, spiritually, and biologically. There
evance of the findings in animal models to human have been a number of different biologic perspec-
gender differences. tives. Each species appears to have a well-defined

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lifespan and pattern of aging. Therefore, it has

Table 1.1 Components of the aging process
been proposed that there is a biologic clock or
genetic program that controls the aging of an At the organ/systems level
organism.3 This was thought to be analogous to the • Neuroendocrine component
well-characterized developmental program of • Immune system component
higher animals that is under tight genetic control. At the cellular level
A number of ‘clocks’ have been proposed for the • Genetic component
regulation of the aging process – the pituitary, the • Cell senescence component
immune system, cellular senescence, etc. Upon
closer investigation, most of these clocks, although At the subcellular level
• Free radical component
they regulate important aspects of the aging
• DNA damage component
process, are the result of aging rather than driving • Glycation component
the aging process itself.
A more recent biologic perspective on why we
age has been articulated by Martin et al.4 ‘There is
no aging program, nor is there an aging gene. One way to think about how we age is shown in
Instead, we age because evolution has no reason to Table 1.1. This structure for thinking about biologic
protect us against unwelcome actions of multiple aging has been followed by Robert Arking7 and
genes late in life.’ In terms of our genes, there are Weinert and Timiras.8 Aging takes place at three
two processes potentially working against increased major levels of biologic organization – at the organ/
longevity.5,6 First, there is selective pressure for systems level, at the cellular level, and at the sub-
genes with beneficial effects early in the lifespan. cellular level. At each of these levels there are com-
Second, there is a lack of selective pressure against ponents of the aging process – changes that
genes which have negative effects late in the lifes- contribute to the aging process we observe.
pan. On the other hand, the idea that aging is pro- However, they are not, in themselves, the whole
grammed for the benefit of the species as a whole picture. Previously, each of these components would
has been recently re-examined.1 be seen as competing theories of aging.
At the organs/systems level we have a neuroen-
How do we age? docrine component and an immune component.
There has been a tendency in aging research to find There are also other systems that ‘age’, but these are
the one theory that accounts for all that we see in some well-studied examples. At the cellular level,
terms of the biology of aging. Perhaps this thinking there is the cell senescence component and the
is a holdover from looking for the biologic clock or genetic component. In reality, the genetic compo-
pacemaker of aging. Thus, there was the neuroen- nent can profoundly affect all three levels, but it is
docrine theory of aging, the cell senescence theory put here for convenience. Finally, there is the sub-
of aging, and the free radical theory of aging. The cellular level, which has the free radical compo-
early proponents of these theories tended to regard nent, the DNA damage component, and the
them as universal theories, explaining all of aging. glycation component..
However, it may be that aging is not something that
is programmed but rather something that happens
because it is not selected against. Then the aging What is the relationship of aging
process becomes much more difficult to generalize. to disease?
Aging may vary by species and within the organs in What is the relationship of these three levels to
a given species. It may also happen at multiple lev- each other and to age-related diseases? The effects
els in a given species – at the organ/systems level, at of aging can manifest themselves independently at
the cellular level, and at the subcellular level. any level of biologic organization. However, they

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also affect the other levels. For example, free radical A second important system is the growth hormone/
production at the subcellular (mitochondrial) level insulin/insulin-like growth factor (IGF) system. In
may ultimately lead to effects at the cellular level. terms of circulating hormones, there is a decrease in
These cellular effects could include cell senes- growth hormone and IGF-1 with age. This may
cence, premature cell death, or uncontrolled cell partly explain the decreased muscle mass and
growth (cancer). These cellular effects could cause increase in frailty seen in the elderly. This has been
deleterious effects at the organ/system level, as in termed the somatopause. In mice, perturbation of
the case of tumors caused by uncontrolled cell this system can markedly increase lifespan, although
growth. However, there can also be independent it usually results in a dwarf appearance as well.10 This
changes at the organ/systems level, such as the system has been implicated in the gender differences
build-up of plaque with time in the circulatory sys- seen in the aging of fruit flies and mice.
tem. There is some evidence, though, that even Steroid hormone production by the adrenal
plaque build-up is the result of cellular changes in gland is a third neuroendocrine system that under-
the endothelial cells lining the circulatory system. goes major age-related changes. The production of
With regard to disease, disease and death are the dehydroepiandrosterone (DHEA), an important
outcomes of the basic biologic processes that occur steroid hormone precursor, declines with age. This
during aging. Aging is not just the sum of all age- occurs despite normal levels of ACTH and cortisol,
related diseases. According to Arking, ‘the com- and it has been termed the adrenopause. In
mon age-related diseases … highlight the weak humans, differences in the cortisol/ACTH ratio
points of the evolved anatomical and physiological may contribute to gender differences in aging
design of the organism.’ 7 (Chapter 2).
These neuroendocrine changes with age have
been well documented and are important character-
The components of aging istics of the aging process. Their effects can be
reversed or moderated by hormone replacement
Aging at the organ/systems level therapy in appropriate situations. However, these
The neuroendocrine component neuroendocrine changes do not direct the aging
The neuroendocrine system is an integral part of process, and hormone replacement therapy does not
the body’s homeostatic mechanisms. It regulates necessarily extend maximal lifespan.11
reproduction, growth, and response to stress among
many other things. Modulation of this system can The immune component
markedly affect longevity and the expression of age- Age-related changes in the immune system have
related diseases. There are three major hormonal been well documented in humans and experimental
systems whose function changes with age.9 These animals. These changes include the involution of
are the reproductive system, the growth regulatory the thymus gland and a decrease in the number and
system, and the stress response system. function of specific immune cell types.12 These
In terms of reproduction, women undergo the physiologic changes may account for the increase in
rapid loss of estrogens at menopause. Men undergo a number of diseases seen in the elderly. The altered
a slower loss of testosterone that has been termed T-cell number and function may result in a greater
the andropause. Many of the gender differences in incidence of infection. Altered B-cell response to
longevity and age-related diseases have been attrib- stimuli may result in increased autoimmune disease.
uted to these two hormones (see Chapter 2). In The increased risk for cancer in the elderly has also
some cases, these hormones may work indirectly to been attributed to decreased immune surveillance.
modulate the aging process. For example, some of However, other risks for cancer include increased
the beneficial effects of estrogen may be due to its free radical damage and altered regulation of cell
stimulation of antioxidant defenses. division (see below).

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Age-related changes in the human immune system fibroblasts would only divide a finite number of times
have been studied with regard to gender differences in despite optimal growth conditions. Initially, there
aging (Chapter 2). Age-related changes in immune were a number of experimental correlations that sug-
function are an important manifestation of the aging gested that limits on cell replication might be related
process. However, like the neuroendocrine changes, to aging of the whole organism. The correlations
they do not drive the aging process. Even organisms included the fact that the number of population dou-
with poorly developed immune systems age. blings correlated inversely with donor age, correlated
directly with the longevity of donor species, and was
Aging at the cellular level decreased in Werner’s and progeric patients.
The genetic component Because of these correlations there was an
Aging clearly has a genetic component as demon- intense effort to determine what regulated the num-
strated by ‘twins’ studies. In addition to more subtle ber of cell divisions. It was found that telomeres,
effects, even single gene mutations can produce cat- structures found on the tips of chromosomes that
astrophic phenotypes that seem to mimic the aging serve a protective function, play a major role in
process in a very compressed lifespan. Two of these determining the number of cell divisions.18 With
diseases are Werner’s syndrome and Hutchinson– each cell division, the telomeres shorten, and even-
Gilford progeria. The defect in Werner’s syndrome tually they reach a point where cell division is
was found to be single-base mutations in the gene halted. The importance of telomeres was further
coding for a DNA helicase.13 Helicases are enzymes underscored with the discovery of telomerase, an
that are involved in the unraveling of double- enzyme found in germ line and immortalized cells.
stranded DNA for transcription or replication. The Telomerase repairs the telomere shortening that
defect in Hutchinson–Gilford progeria was found to takes place after each cell division and so delays cell
be in lamin A.14 This protein is a structural compo- senescence.19
nent of the cell nucleus. However, with additional research it has
The potential for genetic modification of the become clear that telomeres and telomerase are not
lifespan in mammals has been shown by a number the sole regulatory factors. It has been shown that
of spontaneous and engineered modifications of cells undergo stress-induced as well as replicative
the growth hormone/insulin/IGF system.10 senescence.20 There are also a number of different
Although such modifications result in markedly factors and cellular pathways that interact to
increased lifespans, they usually result in undesir- induce cell senescence.21 Some of these other fac-
able phenotypic characteristics as well. These tors are oxidative stress and DNA damage (see
include stunted growth and decreased reproductive below). These factors may affect telomere length
function. More recently, other strategies have been directly, as well as work through other mechanisms
used to increase the mouse lifespan. These include to induce senescence.
deleting the insulin receptor from adipose tissue15 Telomere length and cell senescence may play a
and overexpressing mitochondrial catalase, an role in certain tissues in human aging. They may con-
important antioxidant enzyme.16 As interesting as tribute to gender differences (see Chapter 2).
these transgenic mouse models are, it is not clear However, telomere shortening with age has been dif-
whether humans have a similar potential for lifes- ficult to observe in rodents, except in some circum-
pan extension. It is also not clear whether such stances. In addition, cell senescence would not be
extension could be achieved without undesirable expected to play a role in the aging of organs com-
side-effects. prised mostly of non-dividing cells, such as the brain.

Aging at the subcellular level

The cell senescence component The free radical component
The fact that cells senesce was originally observed by The link between free radicals, which are highly
Leonard Hayflick.17 Hayflick found that human skin reactive chemical compounds, and aging was first

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proposed by Harmon.22 The free radical theory for cellular metabolism, these subcellular
states in general terms that free radicals within the organelles have been extensively studied for their
body cause oxidative damage to cellular molecules – role in biological aging. These observations are
proteins, DNA, lipids, etc.23 This molecular damage sometimes referred to as the ‘mitochondrial theory
eventually causes cellular dysfunction such as cell of aging’.31 Mitochondria in older aerobic tissue
death (necrosis), premature cell senescence (see such as skeletal muscle tend to be fewer in number
above), premature programmed cell death (apopto- and have an altered appearance. They produce less
sis), and uncontrolled cell growth (cancer). These energy and more free radicals as the energy-pro-
cellular changes then lead to decreased organ func- ducing reactions become less efficient. Oxidative
tion, decreased regulatory systems function, and damage to mitochondrial proteins and DNA has
ultimately death. Initially, it was felt that most free been shown to increase with age.32 Mitochondrial
radical production in the body came from external DNA codes for some of the proteins involved in
sources such as ionizing radiation or environmental energy production. It has been suggested that this
pollutants. However, recently the focus has been on leads to a downward spiral as far as mitochondrial
free radicals produced by normal cellular functions function is concerned. Increased free radical pro-
such as energy production by mitochondria and the duction leads to increased damage to mitochondr-
reaction mechanisms of certain enzymes. ial DNA and proteins, which, in turn, leads to
There are several lines of evidence supporting decreased energy production and more free radical
the importance of the free radical component of production.
aging. First, oxidative damage to DNA, proteins, Because free radicals can cause so much disrup-
and lipids has been shown to increase with age in tion of cellular function, it has become increasingly
experimental animals.24 Because free radical damage clear that there are extensive cellular mechanisms
results mostly in oxidative damage, the free radical for the neutralization of free radicals. Oxygen free
theory is sometimes referred to in more general radicals generated by mitochondria and enzymatic
terms as the ‘oxidative stress’ theory. Second, longer reactions are converted to hydrogen peroxide by the
lived species are less susceptible to oxidative stress enzyme superoxide dismutase (SOD). Hydrogen per-
than shorter lived species25 and have more efficient oxide is then converted to water by two pathways.
repair mechanisms.26 Third, a high metabolic rate, One pathway is via the enzyme catalase. The second
which generates more free radicals, is associated pathway is via the glutathione cycle. Glutathione is
with a shorter lifespan. This correlation formed the constantly reduced (via glutathione reductase) and
basis for the ‘rate of living’ theory of aging which then re-oxidized (via glutathione peroxidase). In the
was proposed a number of years ago.27 Fourth, process it converts hydrogen peroxide to water. The
organisms engineered to have higher antioxidant protein components of these free radical defense
defenses live longer. This has been shown in a num- pathways are under genetic control.
ber of organisms including fruit flies,28 round- The free radical component of aging plays a major
worms,29 and mice.16 role in other subcellular components of aging – the
A final piece of evidence supporting the impor- DNA damage component and the glycation com-
tance of free radicals in aging comes from dietary ponent (see below). Together they play an impor-
restriction studies. Dietary restriction is feeding ani- tant role in the biology of aging. However, it is still
mals less food than they would normally eat.30 It has not clear whether oxidative damage accounts for all
been demonstrated to increase mean and maximal of the features of aging.8 The fact that the free rad-
lifespan in a diverse number of organisms, including ical defenses are under genetic control underscores
worms, flies, yeast, mice, and rats. The increased the potential importance of other mechanisms.
longevity induced by dietary restriction is associated Nevertheless, many of the gender differences in ani-
with decreased oxidative damage.24 mal models of aging are explained in terms of dif-
Since mitochondria generate much of the free ferences in free radical production and free radical
radical load of the cell, as well as producing energy defense pathways (see below).

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The DNA damage component differences in particular.35 It has a short lifespan, it is

One of the molecular structures most sensitive to easy to manipulate genetically, and it has distinct
free radical damage is DNA. This includes the DNA male and female sexes. The female of several species
found in nuclear chromosomes as well as the circu- lives longer than the male.36,37 In addition, the
lar DNA found in mitochondria. The damage to females show a much greater response to dietary
chromosomal DNA includes strand breaks, cova- restriction in terms of increased lifespan.36
lent modifications, and chromosomal rearrange- Several factors have been cited as contributing to
ments. It has been proposed that such damage may these gender differences. First, there may be intrin-
result in altered gene expression and contribute to sic genetic differences in the way that longevity is
the aging process.33 It is not clear how much these regulated in male and female flies. A genome-wide
events contribute to the global aging process. Much screen for regions of DNA (quantitative trait loci)
DNA damage is in the form of chromosomal that affect longevity found that these regions had
rearrangements. Such rearrangements are usually sex-specific effects.38
associated with diseases such as cancer rather than Second, there may be gender differences in the
with aging. As mentioned above, damage to mito- insulin/IGF signaling (IIS) pathway.39 Mutation of
chondrial DNA has been most thoroughly studied this pathway increases the lifespan of female flies
as a manifestation of free radical damage. It may be much more than male flies. In fact, very strong
in this context that DNA damage is most impor- mutations in this pathway decrease male longevity
tant. Alteration of mitochondrial DNA replication while increasing female longevity. This suggests that
leads to a premature aging phenotype in mice.34 the IIS pathway is more active in normal female
flies compared to males. Differences in the IIS sys-
The glycation component tem may also explain the fact that females show a
The glycation component of aging arises from the greater response to dietary restriction.36
non-enzymatic combining of glucose with proteins. Finally, the greater female response to dietary
A common example of this is the high amount of restriction may reflect the fact that female flies have
hemoglobin that is glycosylated in the blood of dia- a higher nutrient demand than male flies due to egg
betics. This non-enzymatic glycosylation results in production.36 Dietary restriction reduces egg pro-
the formation of AGEs (advanced glycation end duction and this may increase longevity. There is
products). This process increases with age because generally an inverse relationship between reproduc-
the glycation reaction is accelerated by free radicals. tion and longevity.
This ties glycation in with the free radical compo- These gender differences in the effect of dietary
nent of aging. Glycation again is not a universal restriction have been generalized to other longevity-
explanation but may play an important role in the extending manipulations in flies. In a survey of the
aging of certain tissues. Proteins which have been literature, Burger and Promislow40 found that these
shown to be glycosylated include collagen, vascular manipulations tended to favor females over males in
proteins, and lens crystallin proteins. The glycosyla- reports where both sexes were studied. In addition
tion of these proteins could play a role in the aging to the factors mentioned above (genetic, IIS path-
of connective tissue, blood vessels, and the lens of way and reproductive needs), the authors also cite
the eye, respectively. the fact that females have two X chromosomes
while males have an X and a Y. In male flies, most
genes on the X chromosome are overexpressed to
Gender differences in animal model offset the fact that there is only one X chromosome.
longevity Anything that modifies this process could lead to
gender effects affecting longevity.
Fruit fly In summary, gender differences in fruit fly longevity
The fruit fly has many advantages as a model organ- could be due to sex-linked genetic differences, differ-
ism for the study of aging in general and gender ences in the insulin/IGF signaling pathway, the greater

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increased both male and female lifespan.41

Table 1.2 Biologic basis of gender differences
However, the shorter-lived males showed a greater
Fruit flies percentage increase to the point that their lifespan
• Sex-linked genetic differences was now equal to the females’. In a third study, the
• Insulin/IGF signaling pathway insulin receptor in fat tissue was deleted.15 This mod-
• Female reproductive needs ification produced similar increases in longevity in
• Sex chromosome differences (XX vs XY) both sexes.
Mice One study in mice has looked at the interaction
• Insulin/IGF signaling pathway between estrogen and insulin in regulating resis-
• Reduced glucose tolerance in males tance to oxidative stress in males and females.43
• Elevation of antioxidant pathways Insulin action was reduced by making mutant mice
by estrogen with reduced levels of the insulin receptor. When
• Telomere length (?) subjected to oxidative stress, mutant female mice
Rats survived significantly longer than males. Relative to
• Greater free radical production in males this, the mitochondrial superoxide dismutase (SOD)
• Elevation of antioxidant pathways activity in the liver was elevated in the female
by estrogen mutant mice relative to the normal animals. There
• Telomere shortening was no elevation of SOD activity in the mutant
Humans (from Chapter 2) male mice. These studies also indicated a role for
• Sex chromosome differences (XX vs XY) estrogen in these gender differences. When estrogen
• Elevation of antioxidant pathways was administered to mutant mice, it increased their
by estrogen resistance to oxidative stress. Conversely, ovariec-
• Telomere length tomy reduced resistance to oxidative stress. Both
• Stress hormones (cortisol/ACTH) these changes correlated with changes in mitochon-
• Immune function drial SOS activity. One limitation of these studies is
that they were performed in 4-month-old mice and
longevity itself was not measured.
In terms of mechanisms, several studies have
reproductive needs of females, and differences in sex
reported that the antioxidant pathways in female
chromosomes (Table 1.2).
mice are more robust than in male mice. The glu-
tathione content of most tissues declines with age
Mice more rapidly in male mice than in female mice, due
In general, female mice tend to live longer than to decreased synthesis.44 In the mouse brain, cata-
male mice, but the magnitude of this effect is lase and glutathione activity are higher in old
dependent on the strain.41 In some strains the rela- female mice compared to male mice, which corre-
tionship is reversed.42 A number of mice have been lates with higher levels of lipid peroxidation in male
characterized that have either a spontaneously mice.45 The increased activity of female antioxidant
occuring or targeted mutation that interferes with pathways may underlie the finding that the hearts
the growth hormone/IGF system.10 In some cases of old female mice are more tolerant of ischemic
these mutations show gender effects and in some insult than are the hearts of old males.46
cases not. In mice where the IGF-1 receptor was Finally, in humans it has been proposed that dif-
partially inactivated, female mice showed a signifi- ferences in telomere length may underlie gender dif-
cant increase in lifespan while males did not.42 The ferences (see Chapter 2). In mice, telomeres are much
authors discuss these gender differences in terms of longer than in humans, and it has been difficult to
reduced glucose tolerance and decreased resistance relate telomere shortening to the aging of individual
to oxidative stress in males. In another study, delet- organs or longevity in general. However, in one study
ing the growth hormone receptor significantly using a strain of mice with short telomeres, female

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Textbook of health in aging men

mice had significantly longer telomeres than males was associated with an increase in the cellular
over the whole lifespan in a number of tissues.47 pathway that leads to cell senescence. These
In summary, factors that could contribute to gen- changes correlated with age-related changes in renal
der differences in mouse longevity include differ- function, which were much more severe in the male.
ences in the insulin/IGF signaling pathway, such as What is the source of these gender differences in
is seen in fruit flies. However, they also include hor- mitochondrial antioxidant defenses? These investiga-
monal factors such as reduced glucose tolerance in tors make the case that estrogen is responsible for the
males, and elevation of antioxidant pathways by increased expression of antioxidant enzymes.48 They
estrogen, leading to increased resistance to oxida- have shown that in a mammary gland tumor cell line
tive stress (Table 1.2). The longer telomeres in estrogen can increase expression of SOD and glu-
female mice may also be a factor, but this is difficult tathione peroxidase and reduce hydrogen peroxide
to interpret, since the regulation of telomere length concentrations.52 To show the relevance of this in
and its relationship to aging is markedly different in intact rats, they have used ovariectomized rats with
the mouse compared to humans. and without estrogen treatment. Ovariectomy signif-
icantly increased mitochondrial hydrogen peroxide
Rats production while estrogen treatment reduced it back
Gender differences in the longevity of Wistar rats to normal.48 Thus, the gender differences seen in rat
have been studied extensively by Vina and col- longevity may involve differences in the expression
leagues.31,48 The female Wistar rat lives longer, and of free radical defenses as modulated by estrogen.
they have studied this in terms of free radical pro- In summary, factors that could contribute to gen-
duction and free radical defenses.48 Mitochondrial der differences in rat longevity focus on free radical
hydrogen peroxide production is less and free radi- damage and its modulation by estrogen. These fac-
cal defenses are elevated in female livers.49 The con- tors include increased free radical production in
centration of glutathione in males is about half that males, increased antioxidant activities in females,
of females in mitochondria. The activity of mito- and a positive effect of estrogen in decreasing free
chondrial SOD in females is about twice that of radical production and increasing antioxidant path-
males,49 and others have shown that glutathione ways (Table 1.2). Increased oxidative damage may
peroxidase activity is also elevated.50 Finally, mito- also contribute to the telomere shortening reported
chondrial cytochrome c oxidase activity, an impor- in the rat kidney. The gender differences in the
tant component of the respiratory chain, is higher insulin/IGF pathway seen in fruit flies and mice
in females than males.48 have not been studied in the rat due to the difficulty
The net result of these gender differences is that of performing genetic manipulation in the rat.
male mitochondria produce more free radicals. At
the same time, they have less efficient mechanisms
for getting rid of them than do female mitochon- Relevance to human longevity
dria.31 One evidence of this is that oxidative damage
to mitochondrial DNA has been found to be 4-fold What is the relevance of these studies to human gen-
higher in males than in females.48 der differences? The biologic basis of human gender
The gender differences in the aging Wistar rat differences is discussed in Chapter 2. Some of the
have been pursued in more detail by looking specifi- factors contributing to human gender differences
cally at the aging kidney.51 Studying the kidney is are listed in Table 1.2 (bottom). Many of these fac-
important, since kidney disease is a major cause of tors have also been identified in the model systems
death in rats. As reported above for the liver, signif- discussed in this chapter. These include differences
icantly higher levels of antioxidant enzymes were in sex chromosome expression, elevation of antioxi-
seen in the older female kidney compared to the dant defenses by estrogen, and perhaps telomere
male. In addition, a greater degree of telomere short- length. Other factors that may play a role in human
ening was seen in the male with age. This shortening longevity differences include stress hormone levels

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The biology of gender differences in animal models of aging

and immune function. Stress hormones and immune 8. Weinert BT, Timiras PS. Invited review: theories of
function have been well studied in rats and mice as aging. J Appl Physiol 2003; 95: 1706–16.
9. Lamberts SWJ, van den Beld AW, van der Lely AJ.
a function of age. Therefore, these rodents would be
The endocrinology of aging. Science 1997; 278:
excellent model systems in which to study the con- 419–24.
tribution of the neuroendocrine and immune sys- 10. Bartke A. Minireview: role of the growth
tems to gender differences in longevity. hormone/insulin-like growth factor system in mam-
As we stated in the beginning of this chapter, malian aging. Endocrinology 2005; 146: 3718–23.
11. Olshansky SJ, Hayflick L, Carnes BA. Position state-
recent comparative studies of aging in model organ-
ment on human aging. J Gerontol A Biol Sci Med
isms indicate that they have many characteristics of Sci 2002; 57: B292–7.
aging in common. At the biologic level, there 12. Ernst DN, Hobbs MV. Age-related changes in
appear to be common biochemical pathways that cytokine expression by T cells. In: Morley JE,
modulate aging in these organisms. These pathways Armbrecht HJ, Coe RM, Vellas B, eds. The
Science of Geriatrics. Paris: Serdi Publisher, 2000:
regulate growth, glucose metabolism, and resistance
541–54.
to oxidative damage.1 As we have outlined in this 13. Yu CE, Oshima J, Fu YH et al. Positional cloning of
chapter, gender effects in model organisms can be the Werner’s syndrome gene. Science 1996; 272:
understood in terms of gender differences in these 258–62.
pathways. These pathways have their counterparts 14. Eriksson M, Brown WT, Gordon LB, Glynn MW,
Singer J, Scott L, Erdos MR, Robbins CM, Moses TY,
in humans. However, further work is needed to
Berglund P, Dutra A, Pak E, Durkin S, Csoka AB,
determine the degree to which these pathways mod- Boehnke M, Glover TW, Collins FS. Recurrent de
ulate human aging and the marked gender differ- novo point mutations in lamin A cause
ences that characterize it. There is every reason to Hutchinson–Gilford progeria syndrome. Nature
expect that as we learn more about the biologic basis 2003; 423: 293–8.
15. Bluher M, Kahn BB, Kahn CR. Extended longevity
of aging, we will be able to better understand gender
in mice lacking the insulin receptor in adipose tissue.
differences. Likewise, the gender differences them- Science 2003; 299: 572–4.
selves will give insight into which mechanisms are 16. Schriner SE, Linford NJ, Martin GM, Treuting P,
important in terms of modulating the aging process. Ogburn CE, Emond M, Coskun PE, Ladiges W, Wolf
N, Van RH, Wallace DC, Rabinovitch PS. Extension
of murine life span by overexpression of catalase tar-
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17. Hayflick L, Moorehead PS. The serial cultivation of
1. Longo VD, Mitteldorf J, Skulachev VP. Opinion: human diploid cell strains. Exp Cell Res 1961; 25:
programmed and altruistic ageing. Nat Rev Genet 585–621.
2005; 6: 866–72. 18. Campisi J. Cancer, aging and cellular senescence. In
2. Miller RA. The biology of aging and longevity. In: Vivo 2000; 14: 183–8.
Hazzard WR, Blass JP, Ettinger WH, Halter JB, 19. Bodnar AG, Ouellette M, Frolkis M, Holt SE, Chiu
Ouslander JG, eds. Principles of Geriatric Medicine and C, Moran GB, Harley CB, Shay JW, Lichsteiner S,
Gerontology. New York: McGraw-Hill, 1998: 3–19. Wright WE. Extension of life span by introduction of
3. Hayflick L. How and Why We Age. New York: telomerase into normal human cells. Science 1998;
Ballantine, 1994. 279: 349–52.
4. Martin GM, Austad SN, Johnson TE. Genetic analy- 20. Marcotte R, Wang E. Replicative senescence revis-
sis of ageing: role of oxidative damage and environ- ited. J Gerontol A Biol Sci Med Sci 2002; 57:
mental stresses. Nat Genet 1996; 13: 25–34. B257–69.
5. Kirkwood TBL. Comparative and evolutionary 21. Campisi J. Senescent cells, tumor suppression, and
aspects of longevity. In: Finch CE, Schneider EL, eds. organismal aging: good citizens, bad neighbors. Cell
Handbook of the Biology of Aging. New York: Van 2005; 120: 513–22.
Norstrand Reinhold, 1985: 27–44. 22. Harmon D. Aging: a theory based on free radical and
6. Austad SN. What evolution explains about aging. In: radiation chemistry. J Gerontol 1956; 2: 298–300.
Austad SN, ed. Why We Age. New York: John 23. Finkel T, Holbrook NJ. Oxidants, oxidative stress and
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7. Arking R. Biology of Aging: Observations and 24. Sohal RS, Weindruch R. Oxidative stress, caloric
Principles. Oxford: Oxford University Press, 2006. restriction, and aging. Science 1996; 273: 59–63.

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25. Agarwal RS, Sohal RS. Relationship between suscep- 40. Burger JM, Promislow DE. Sex-specific effects of
tibility to protein oxidation, aging, and maximum life interventions that extend fly life span. Sci Aging
span potential of different species. Exp Gerontol Knowl Environ 2004; e30: 2004.
1996; 31: 365–72. 41. Coschigano KT, Holland AN, Riders ME, List EO,
26. Hart RW, Setlow RB. Correlation between deoxyri- Flyvbjerg A, Kopchick JJ. Deletion, but not antago-
bonucleic acid excision repair and lifespan in a num- nism, of the mouse growth hormone receptor results
ber of mammalian species. Proc Nat Acad Sci USA in severely decreased body weights, insulin, and
1974; 71: 2169–73. insulin-like growth factor I levels and increased life
27. Pearl R. The Rate of Living. London: University of span. Endocrinology 2003; 144: 3799–810.
London Press, 1928. 42. Holzenberger M, Dupont J, Ducos B, Leneuve P,
28. Orr WC, Sohal RS. Extension of life-span by overex- Geloen A, Even PC, Cervera P, Le BY. IGF-1 recep-
pression of superoxide dismutase and catalase in tor regulates lifespan and resistance to oxidative
Drosophila melanogaster. Science 1994; 263: 1128–30. stress in mice. Nature 2003; 421: 182–7.
29. Melov S, Ravenscroft J, Malik S, Gill MS, Walker 43. Baba T, Shimizu T, Suzuki Y, Ogawara M, Isono K,
DW, Clayton PE, Wallace DC, Malfroy B, Doctrow Koseki H, Kurosawa H, Shirasawa T. Estrogen,
SR, Lithgow GJ. Extension of life-span with superox- insulin, and dietary signals cooperatively regulate
ide dismutase/catalase mimetics. Science 2000; 289: longevity signals to enhance resistance to oxidative
1567–9. stress in mice. J Biol Chem 2005; 280: 16417–26.
30. Masoro EJ. Overview of caloric restriction and age- 44. Wang H, Liu H, Liu RM. Gender difference in glu-
ing. Mech Ageing Dev 2005; 126: 913–22. tathione metabolism during aging in mice. Exp
31. Vina J, Sastre J, Pallardo F, Borras C. Mitochondrial Gerontol 2003; 38: 507–17.
theory of aging: importance to explain why females 45. Sobocanec S, Balog T, Sverko V, Marotti T. Sex-
live longer than males. Antioxid Redox Signal 2003; dependent antioxidant enzyme activities and lipid
5: 549–56. peroxidation in ageing mouse brain. Free Radic Res
32. Mandavilli BS, Santos JH, Van HB. Mitochondrial 2003; 37: 743–8.
DNA repair and aging. Mutat Res 2002; 509: 127–51. 46. Willems L, Zatta A, Holmgren K, Ashton KJ,
33. Vijg J, Gossen JA. Somatic mutations and cellular Headrick JP. Age-related changes in ischemic toler-
aging. Comp Biochem Physiol 1993; 104B: 429–37. ance in male and female mouse hearts. J Mol Cell
34. Kujoth GC, Hiona A, Pugh TD, Someya S, Panzer K, Cardiol 2005; 38: 245–56.
Wohlgemuth SE, Hofer T, Seo AY, Sullivan R, 47. Coviello-McLaughlin GM, Prowse KR. Telomere
Jobling WA, Morrow JD, Van RH, Sedivy JM, length regulation during postnatal development and
Yamasoba T, Tanokura M, Weindruch R, ageing in Mus spretus. Nucleic Acids Res 1997; 25:
Leeuwenburgh C, Prolla TA. Mitochondrial DNA 3051–8.
mutations, oxidative stress, and apoptosis in mam- 48. Vina J, Borras C, Gomez-Cabrera MC, Orr WC. Part
malian aging. Science 2005; 309: 481–4. of the series: from dietary antioxidants to regulators
35. Partridge L, Piper MD, Mair W. Dietary restriction in in cellular signalling and gene expression. Role of
Drosophila. Mech Ageing Dev 2005; 126: 938–50. reactive oxygen species and (phyto)oestrogens in the
36. Magwere T, Chapman T, Partridge L. Sex differences modulation of adaptive response to stress. Free Radic
in the effect of dietary restriction on life span and Res 2006; 40: 111–9.
mortality rates in female and male Drosophila 49. Borras C, Sastre J, Garcia-Sala D, Lloret A, Pallardo
melanogaster. J Gerontol A Biol Sci Med Sci 2004; FV, Vina J. Mitochondria from females exhibit higher
59: 3–9. antioxidant gene expression and lower oxidative dam-
37. Davies S, Kattel R, Bhatia B, Petherwick A, age than males. Free Radic Biol Med 2003; 34: 546–52.
Chapman T . The effect of diet, sex and mating sta- 50. Pinto RE, Bartley W. Changes in glutathione reduc-
tus on longevity in Mediterranean fruit flies tase and glutathione peroxidase activities in rat liver
(Ceratitis capitata), Diptera: Tephritidae. Exp related to age and sex. Biochem J 1968; 109: 34P.
Gerontol 2005; 40: 784–92. 51. Tarry-Adkins JL, Ozanne SE, Norden A, Cherif H,
38. Nuzhdin SV, Pasyukova EG, Dilda CL, Zeng ZB, Hales CN. Lower antioxidant capacity and elevated
Mackay TF. Sex-specific quantitative trait loci affect- p53 and p21 may be a link between gender disparity in
ing longevity in Drosophila melanogaster. Proc Natl renal telomere shortening, albuminuria, and longevity.
Acad Sci USA 1997; 94: 9734–9. Am J Physiol Renal Physiol 2006; 290: F509–16.
39. Clancy DJ, Gems D, Harshman LG, Oldham S, 52. Borras C, Gambini J, Gomez-Cabrera MC, Sastre J,
Stocker H, Hafen E, Leevers SJ, Partridge L. Pallardo FV, Mann GE, Vina J. 17Beta-oestradiol up-
Extension of life-span by loss of CHICO, a regulates longevity-related, antioxidant enzyme
Drosophila insulin receptor substrate protein. expression via the ERK1 and ERK2[MAPK]/
Science 2001; 292: 104–6. NFkappaB cascade. Aging Cell 2005; 4: 113–8.

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CHAPTER 2

The biologic basis for longevity

differences between men and women
Rafi T Kevorkian and Oscar A Cepeda

Introduction playing an important role in determining the

gender-specific probability of achieving longevity.1
In the modern world much has changed over the
last 50 years. Lifestyles have become healthier with
emphasis on regular exercise, healthy diets, and a Epidemiology
declining dependence on tobacco. As a result, life
expectancy has also changed, rising slowly but in a The gender gap in human beings tends to change
steady manner year after year. In the Western world, depending on biologic and socio-cultural issues. Life
the average lifespan is 73.7 years for men and 83.8 expectancy is different across countries and it is
years for women. People of both sexes live longer, related in some way to the level of development in
but every year women have outpaced men. Life each region of the world.2 Nations struggling with
expectancy is roughly 7 years longer for women poverty and underdevelopment have a limited life
than for men. Although women live longer than expectancy for women, mainly because of a high
men, they do so with greater time spent with dis- maternal mortality, making the difference between
ability. This chapter will examine the biologic rea- genders less evident. The opposite situation is
sons why women outlive men. observed in developed countries such as Sweden,
Aging could be defined as a normal process of Canada, Western Europe, and the United States,
every living cell, arising from metabolic changes where great improvements in public health and
leading to a functional decline, and is associated maternal and infant mortality have been made,
with structural impairment of somatic tissues. Aging leading to a substantially higher life expectancy and
and gender have been studied for several decades a marked difference in the gender gap of longevity
and it is clear that gender accounts for important that favors women, resulting in a larger number of
differences in the incidence and prevalence of many women surviving the age of 65. The ratio of women
age related diseases. Potentially preventable envi- to men at age 65 is close to 120:100 and by age 85
ronmental causes, such as smoking, alcohol, and is 250:100. This longevity gap persists to very old
dietary behavior, have played an important role in age, even beyond the age of 85, when the average
the large gender differential in some countries. woman outlives the average man by 1.2 years.3
However, several theories for the longevity gender The basis for this gender difference in longevity
gap support a biologic basis for aging, making it a between men and women is thought to be a com-
source of endless debate due to the complex interac- plex interaction of environmental, behavioral, and
tion of environmental, historic, and genetic factors biologic factors. Major causes of mortality and death

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rates are higher in men. Mortality from cardiovascu- is that frailer individuals drop out of the population,
lar disease is more likely to occur in men than in leaving behind a more robust cohort that continues
women (173.1 per 100 000 vs 95.4 per 100 000);1,3 to survive.6
whereas the rate of stroke is 20% higher in men.
However, cardiovascular disease remains the lead-
ing cause of death in older women, exceeding the Genetic differences in human
number of deaths in older men in terms of absolute longevity
number of cardiovascular deaths.
The incidence of cancer is higher in men com- Aging could be considered a result of the interac-
pared to women, and this difference is most evident tion between genes and environment, in which
after 64 years of age. There is a sharp rise in cancer genetics becomes a powerful tool to understand the
incidence after the age of 64 for both men and fundamental mechanisms of aging since it deals
women, but it is higher for men (559.6 per 100 000 with the blueprints for life that we inherit. The rate
men vs 420.1 per 100 000 women). Among elderly of aging and maximum lifespan vary among species,
men, three cancers account for 50% of all malignan- and therefore must be at least partly under genetic
cies: prostate, lung, and colon cancer. Lung cancer control.7 Variation in human longevity has a very
is the most common malignant entity in both men strong genetic basis. A Scandinavian study of
and women over age 60 and is responsible for 30% monozygotic and dizygotic twins calculated the her-
of all cancer deaths in this group. The second and itability of life expectancy to be to be 20 to 30%,8
third highest rates of incidence for cancer are breast and this could in some way be the reason why cases
and colorectal cancer for women, and colorectal of exceptional longevity tend to cluster in families.
and prostate for men.4 Although far less common as The familial contribution (some combination of
a cause of death than either cardiovascular disease shared genes and environment) to exceptional
or malignancy, mortality from trauma, as a result of longevity has been explored with centenarian pedi-
accidents or violence, contributes significantly to grees. The survival of siblings of 102 centenarians
the total loss of anticipated life years. was compared with the survival of siblings of a con-
Life expectancy varies throughout the lifespan trol group (n = 77) who were from a similar birth
and actually the gap between men and women is cohort born in 1896 but whose parents had died 27
greatest at younger ages and becomes smaller with years earlier at the age of 73.9 The relative risk of
increasing age. However, the biggest increase in the survival steadily increased with age for siblings of
ratio of females to males occurs at the extremes of the centenarians to the point that they had four
age. Nevertheless, at all ages, women have better times the probability of surviving to age 91. The rel-
survival than do men. At birth the gap is about 6 ative risk for survival to older age continued to rise
years; at age 65 it decreases to about 3 years; and at beyond age 91, although these larger differences
age 75 it is even lower at about 2 years. Nowadays were not statistically significant because of the small
women have an excellent chance to reach the numbers of siblings at these extreme ages.
eighth decade, and for those who reach age 85, the Clinical syndromes that have features of acceler-
remaining average life expectancy is an additional ated aging, such as Werner’s syndrome and
6 years. Demographic trends have shown that at very Hutchinson–Gilford progeria, are characterized by
old age mortality in human beings begins to deceler- mutations in two of the genes involved in the
ate. These trends are based on European calculations metabolism and repair of DNA. Werner’s syndrome
from a database of 70 million people who reached is characterized by mutations in the WRN gene,
the age of 80 and of 200 000 who lived to at least which is thought to be involved in maintaining
100. Research has shown that there is an observed genomic stability. Hutchinson–Gilford disease is
deceleration in mortality rate as age 100 is caused by a mutation in the LMNA gene, which
approached, and it is maintained through age 105 codes for a group of nuclear membrane proteins called
for men and 107 for women.5 One acceptable theory lamins that affect nuclear morphology, chromatin

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structure, DNA synthesis, and gene expression.10 and the cell is no longer able to replicate. The pro-
Another factor related to longevity and genetic dif- gressive shortening of telomeres acts as an inherent
ferences is the apolipoprotein (apo) ε-4 allele drop- replicative clock in which the somatic cell has a
out seen with extreme age as an example of a finite capacity for division (proliferating germ line
polymorphism with an influence powerful enough to cells, lymphocytes, and cancer cells do not undergo
have a noticeable effect upon survival in the general telomeric shortening). Thus, telomere length may
population and across various ethnic lines. Human be an important determinant of replicative capacity,
et al11 noted that the frequency of the ε-4 allele leading to apoptosis or neoplastic transformation.17
decreases markedly with advancing age. Results from Multiple cross-sectional population analyses of
the Italian centenarian study showed an association telomere length in white blood cells have been the
between specific variations in the locus for the apo- main source of information regarding human telom-
B allele and extreme longevity.12 One of its counter- ere dynamics in vivo. Telomere length is highly her-
parts, the ε-2 allele, becomes more frequent with itable,18 and inversely correlated with age, longer in
advanced age among Caucasians. Presumably the adult women than men, and yet equivalent in new-
drop-out at earlier age of the ε-4 allele is because of born boys and girls. Two factors have been identi-
its association with ‘premature’ mortality secondary fied as responsible for the observed longer telomeres
to Alzheimer’s disease and heart disease.13 In another in women, namely estrogen and somatic cell selec-
study, nonagenarian subjects had an extremely low tion. Gender and age considerably influence reac-
frequency of histocompatibility locus antigen tive oxygen species (ROS) metabolism. While the
(HLA)-DRw9 and an increased frequency of DR1. exact mechanisms whereby age modifies ROS
A high frequency of DRw9 and a low frequency of metabolism are poorly defined, the sex effect is
DR1 are associated with autoimmune or immune- largely related to ovarian steroid hormones, partic-
deficiency diseases, which can cause premature ularly estrogen. Estrogen and its derivatives exert an
mortality.14 antioxidant effect via a number of mechanisms,
Genes that reduce the risk of atherosclerosis may including scavenging free radicals, inhibiting free
be more common in centenarians, and two such radical formation, and stimulating enzymes which
genes have been identified. In the first case, a muta- are crucial for free radical detoxification.19
tion in the cholesteryl ester transfer protein Estrogens also stimulate the transcription of the
(CETP) gene leads to larger lipoproteins and a gene encoding the telomerase reverse transcriptase
reduced prevalence of cardiovascular disease,15 and enzyme that adds telomere repeats to chromosome
the second gene has variations for microsomal ends, thereby slowing down the rate of telomere
transfer protein (MTP) – the rate-limiting step in erosion as a result of the oxidative stress. This
lipoprotein synthesis.16 Although such genes may upregulation of telomerase and reduced oxidative
have substantial effects on longevity, they do not damage could be a reasonable explanation for the
appear to modulate the aging process. longer telomeres observed in women as compared
with men. Estrogen also stimulates nitric oxide pro-
duction in vascular endothelial cells, and a study
Regulation of telomere length has shown that nitric oxide stimulates telomerase in
these cells.20 The antioxidant effect of estrogens
The telomere and its potential role in cellular tends to disappear with advancing age in old
senescence has generated excitement in the field of women. However, its premenopausal influence
genetics of aging. Telomeres are tandem repeat could set telomere attrition at a trajectory that
sequences (TTAGGG) of DNA that cap the ends maintains longer telomeres in women throughout
of linear chromosomes. Because typical DNA poly- the entire cycle of life
merases cannot fully duplicate these sequences, The relationships between telomere length and
telomeres shorten with each cell division in somatic indicators of vascular aging and cardiovascular risks
cells. Eventually the chromosomes become unstable in humans have been examined. Two studies found

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that telomere length in white blood cells is lipoproteins (HDLs), and increases low-density
inversely correlated with pulse pressure, and one of lipoproteins, increasing the risk of cardiovascular
these studies showed that this relationship is modi- morbidity and mortality.25 On the other hand, estro-
fied by sex.21 Since pulse pressure increases with age gens have demonstrated effective reductions in LDL
and is an indicator of the biologic aging of central cholesterol and increases in HDL, thus having bene-
arteries, and given that cardiovascular risks are ficial effects on the cardiovascular system, lowering
increased with age, it is logical to propose that bio- morbidity and mortality from cardiovascular diseases
logic aging of individuals with relatively short in women.26 Due to their phenolic structure, estro-
telomeres may be more advanced than their gens exhibit marked antioxidant properties, but not
chronologic age would indicate, and also telomere as a direct chemical antioxidant, since the amount of
length is shorter in patients with atherosclerotic estrogens needed for this action exceeds that
coronary heart disease than in their age-matched observed in normal blood. It seems that estrogens
peers.22 Vascular dementia, which leads to a progres- exert an antioxidant effect rather than upregulating
sive intellectual impairment resulting from cere- the expression of the genes encoding antioxidant
brovascular disease, is frequently observed with enzymes through estrogen receptors and cell signal-
essential hypertension and diabetes mellitus,23 and ing pathways.26
is associated with relatively short telomeres. The primary estrogen produced by the ovaries is
The skewed X-linked selection theory of somatic estradiol, and its antioxidant activity relies on the
cells, as a function of aging, is another factor that activation of mitogen-activated protein kinases
might explain longer telomeres in women as com- (MAPKs) ERK1 and ERK2, that subsequently acti-
pared with men. This has been observed primarily vate the signaling pathway for the nuclear factor
in women older than 60 years. Ninety six percent of kappa B (NFκB), thus behaving as double transgen-
the combined length of telomeres in a newly formed ics leading to increased expression of antioxidant
zygote is contributed by autosomal telomeres, which enzymes glutathione peroxidase and manganese-
suggests that factors on the X chromosome influ- superoxide dismutase (MNSOD).26 Glutathione is a
ence telomere length considerably, modulating the major intracellular antioxidant, with concentra-
functional activity of telomerase or other telomere tions similar to those of glucose, and it constitutes a
length-influencing factors. As women get older, the major low molecular weight thiol in cells.27
two somatic cell populations would be redistributed Glutathione levels have been considered a biologic
toward the population that has comparatively marker of aging, and its level inside the mitochon-
longer telomeres, not only because telomere length dria is directly related to the damage associated with
appears to be influenced by an X-linked gene or the aging process. Mitochondrial concentrations of
genes, but also for the reason that longer telomeres glutathione in males are approximately half that
denote resistance to oxidative stress.24 found in females. The degree of DNA oxidation
increases with aging and the level of 8-oxo-
deoxyguanosine (8-oxo-dG) is an excellent marker
Role of sex hormones controling of oxidative damage to the DNA. Levels of 8-oxo-
aging and longevity dG are 4-fold higher in males than in females.28
Phytoestrogens, natural products that exert an
The role that sex hormones play, estrogen in females estrogen-like effect, could mimic the favorable effect
and testosterone in males, in terms of lifespan of estrogens as an upregulator of antioxidant
differences is widely accepted as a factor for longevity longevity-related genes without the substantial post-
differences.25 The role of testosterone in a decreased menopausal drawbacks of estrogens. Phytoestrogens
lifespan has been explained on the basis of the char- constitute an interesting alternative with very few
acteristics which are particular to the male gender, detrimental effects.29 Genistein is a phytoestrogen
such as competitiveness and aggression. Also testos- present in soy and is able to decrease oxidative
terone decreases blood concentrations of high-density stress at nutritionally relevant concentrations. As

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The biologic basis for longevity differences between men and women

demonstrated by Viña and co-workers,30 the beneficial 4-fold less in females than in males. These differences
effects of genistein are mediated by its interactions may be explained by estrogens. Ovariectomy abol-
with estrogen receptors, and the cell signaling path- ishes the gender differences between males and
ways of MAPKs and NFκB. females, and estrogen replacement rescues the
ovariectomy effect in animal models.25

Mitochondrial theory of aging

Stress resistance
Mitochondria are the intracellular organelles
responsible for oxidative metabolism. More than Early in their history, invertebrates appear to have
90% of the oxygen used by aerobic cells is consumed evolved systems for recognizing environmental con-
in mitochondria. Mammalian cells have several ditions, such as food shortages or adverse tempera-
hundred mitochondria, all of which were inherited tures, which favored differentiation into long-lived
from those in the maternal egg. Each mitochon- stress-resistant forms rather than into more vulner-
drion has a few identical copies of its own circular able breeding forms. These stress-resistance systems
DNA, which codes for 13 mitochondrial enzymes may have been adopted as developmental controls,
involved in cellular respiration (using a slightly dif- for aging pathways by more advanced organisms.
ferent genetic code than does nuclear DNA), and a Several of these genes have human homologs.
few ribosomal and transfer RNA molecules.31 The There is a good correlation between resistance to
rate of mutation of mitochondrial DNA in somatic cytotoxic stress and maximal lifespan in a variety of
cells is about 10 to 20 times faster than nuclear mammals, from hamsters to humans, whose lifespan
DNA, and this could in part be explained because varies 40-fold. Fibroblasts from small, long-lived
mitochondria are an important source of free radi- mice are more resistant to cytotoxic stress than
cals, particularly hydrogen peroxide; hydroxyl radi- those from normal mice.34 The phenomenon of
cals cause oxidative damage to proteins, lipids, and aging, which is characterized by a reduction in the
DNA.25 capability to respond to situations that endanger life
These mutations accumulate with age in postmi- and survival, could be paralleled to the progressive
totic tissues such as neurons, and in cardiac and increase in the level of plasma cath echolamines,
skeletal muscle. The mitochondrial theory of aging inadequate cortisol secretion, decrease in peripheral
is based on the cellular changes that occur at the adrenoreceptor sensitization, reduction in the activ-
level of mitochondrial DNA related to the balance ity of the insulin growth factor-1 (IGF-1) axis, and
between the load of age-related mutations and the decreased secretion of sex steroids as a result of a
healthy inherited DNA. The damage to mitochon- global dysfunction at the level of the hypothal-
drial DNA prevents the regeneration of new mito- amo–pituitary–adrenal axis in response to stress
chondria from postmitotic cells, reducing the level challenges.35
of adenosine triphosphate and consequently cell The response to stress has a clear sexual pattern
death.32 Studies by Sohal and co-workers33 have of differentiation, and it has been attributed to the
shown that shorter-lived species produce higher opposite effects on the cortisol/ACTH balance,
amounts of hydroperoxide than the longer-lived caused by estrogens and androgens. Troiano and co-
species. Females live longer than males in many mam- workers36 showed the sex-related dimorphism is evi-
malian species, including humans. Mitochondria dent until the extreme limits of the human lifespan,
from males produce significantly more hydrogen and that cortisol and ACTH levels at different ages
peroxide (approximately 50%) than those from show different rates of change depending on sex. So
females and have a reduced level of mitochondrial it is not surprising that sex-related differences in the
reduced glutathione, manganese, superoxide dismu- regulation of stress response mediators could play a
tase, and glutathione peroxidase than females. causative role in differing male and female life
Oxidative damage to mitochondrial DNA is also expectancy and longevity.35 Other reports have

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Textbook of health in aging men

shown that the genetic variability of tyrosine males when compared to young males and also
hydroxylase (TH), when compared between cente- elderly females.49 Further research is needed in this
narians and younger persons, showed a considerable field to confirm this association between male
sex-specific TH locus/longevity association.37 A longevity and 8.1AH, which is associated with a
more recent investigation was able to prove that the variety of immune dysfunctions and autoimmune
variability in the mitochondrial genome (mtDNA) diseases. Lagaay et al50 HLA typed 964 Dutch sub-
has a sex-specific impact on longevity. The mtDNA jects (278 males and 686 females) over 85 years,
variant was represented at an expectedly high fre- who were compared with a group of 2444 young
quency among centenarian males.38 adults. A decrease in B40 and an increae in DR-11
(DR5split) in women over 85 years were observed
with an association for longevity for women.
Immunology and longevity Ivanova et al51 studied a group of French centenari-
ans and compared them to an adult control group.
The process of aging imposes changes at all levels in Three differences were noted in three alleles, DR-7,
human beings, and the immune system is no excep- DR-11, and DR-13, that were statistically signifi-
tion. Human immunosenescence is the conse- cant in the older group; DR-11 was higher in
quence of chronic antigenic overload; some of the women.
most important features of age related immune cell
remodelling are: clonal expansion of memory and
effector T-lymphocytes, reduction of naive T cells, Conclusions
and shrinkage of T-cell repertoire. In most elderly
subjects there is an increased plasmatic level of pro- The components of different pathways in women
inflammatory cytokines, despite the lack of clinical and men by which they achieve longevity with and
signs of inflammatory disease,39 which is associated without major age-related disabilities are not com-
with a concomitant alteration of the lipid profile pletely defined yet. Several biologic mechanisms
and an increased capability of activated mononu- could be responsible for the difference between men
clear cells to produce pro-inflammatory cytokines and women. It clear that estrogens play a pivotal
(IL-1, IL-6, TNFα) in comparison with younger role, making women live longer than men, since
individuals. Elevated levels of pro-inflammatory estrogens have effects at the level of cellular oxida-
cytokines are predictors of mortality and morbidity tion and telomere length, and it has also been shown
in the elderly. In particular, ‘high producer’ alleles of that estrogens induce a reduction in LDL cholesterol
pro-inflammatory cytokines have been shown to be and hence in cardiovascular morbidity. Also
associated with inflammatory age-related dis- immune function has some different genetic deter-
eases,40–44 such as Alzheimer’s dementia, and disabil- minants that increase women’s resistance to external
ity,45 and with a decreased probability to reach agressors. However, aging and extreme longevity are
extreme longevity.46 Gene polymorphisms involving not only determined by biologic markers; complex
hemochromatosis,47 and interferon-γ48 have been socio-cultural factors are involved in this process. It
associated with longevity in women but not in men. has been demonstrated that poor socio-economic
Human leukocyte antigen (HLA) is the general conditions are important factors in determining
name of a group of genes in the human major histo- length of survival; careful comparison of data from
compatibility complex (MHC) region on human different countries is necessary to ascertain the roles
chromosome 6 (mouse chromosome 17) that of nature and nurture in this phenomenon which
encodes the cell-surface antigen-presenting pro- plays a complementary role in the aging process.
teins. HLA, besides antigen presentation is respon- Since changes in the environment could trigger
sible for the T-cell repertoire and target cell changes at the molecular-genetic level by inducing
recognition in cytotoxicity. An excess of the 8.1AH mutations, it is possible that this could result in con-
haplotype has been reported in a group of elderly ditions favoring a shorter lifespan.

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The biologic basis for longevity differences between men and women

Changes and manipulation of the aging process 13. Gerdes LU, Jeune B, Ranberg KA et al. Estimation of
will affect the overall risk of developing conditions apolipoprotein E genotype-specific mortality risks
from the distribution of genotypes in centenarians
seen in older people and perhaps will delay the onset
and middle aged men: apolipoprotein E gene is a
of several diseases. The maximal lifespan appears to be frailty gene not a longevity gene. Genet Epidemiol
120 years and the average in developed nations is 2000; 19: 202–10.
about 80 years. Incapacitating conditions particular to 14. Takata H, Suzuki M, Ishi T et al. Influence of major
old people appear at about age 70 or later, and if the histocompatibility complex region genes on human
longevity among Okinawan-Japanese centenarians
human lifespan were increased to 150 years, it is likely
and nonagenarians. Lancet 1997; 2: 824–6.
that debilitating diseases such as Alzheimer’s disease 15. Barzilai N, Atzmon G, Schechter C et al. Unique
would not be noted until age 100, allowing more lipoprotein phenotype and genotype associated with
patients to be free from chronic debilitating illnesses. exceptional longevity. JAMA 2003; 290: 2030–40.
16. Gesaman BJ, Benson E, Brewster SJ et al. Haplotype-
based identification of a microsomal transfer protein
marker associated with the human life span. Proc
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23(2): 343–50. length and possible link to X chromosome. Lancet
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Biodemographic trajectories of longevity. Science 23. Butler RN, Ahronheim J, Fillit H et al. Vascular
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48: B237–44. ory of aging: importance why females live longer than
9. Perls T, Wager C, Bubrick E et al. Siblings of cente- males. Antioxidants and Redox Signaling 2003;
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10. Yu CE, Oshima J, Fu YH et al. Positional cloning of 26. Viña J, Borras C, Gambini J. Why females live longer
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Mitochondrial DNA inherited variants are associated 49. Rea IM, Middleton D. Is the phenotypic combina-
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39. Baggio G, Donazzan S, Monti D et al. Lipoprotein(a) 50. Lagaay AM, D’Amaro J, Ligthart V et al. Longevity
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CHAPTER 3

The biology of the aging brain

Xi Chen and Shirley Shidu Yan

Introduction reveals a ‘classic aging pattern,’ in which there is a

greater decline in the speed-dependent performance
Aging brings about characteristic changes in brain IQ as compared to the vocabulary IQ, and a greater
functions, which can present in such diverse aspects decline in ‘fluid’ (novel solutions) versus ‘crystal-
as alterations in cognitive function, motor coordi- lized’ (old solutions) intelligence. The elderly are
nation, and sleep pattern. Although there is a gen- not as efficient at integrating unfamiliar information
eral trend towards functional decline during aging, or using novel approaches as they are in employing
the degree of these changes can vary widely between old information in old solutions, strategies, or tem-
individuals and generally they do not seriously com- plates (wisdom). Thus, overlearned, well-practiced,
promise the quality of life. However, some age- and familiar skills, ability, and knowledge are ‘crys-
related alterations might increase a person’s tallized’ and continue to be fully operative and even
vulnerability to some neurodegenerative disorders, show gains into the seventies and eighties; while
such as Alzheimer’s disease (AD). Recent advances activities requiring ‘fluid’ intelligence, which
in molecular biology, neurophysiology, and func- involves reasoning and problem solving for unfamil-
tional brain imaging have made a significant iar solutions, follow the typical pattern of relatively
progress in understanding some aspects of the bio- slow decline through the middle years until the late
logical mechanisms underlying the aging process. fifties or early sixties, when decline proceeds at an
increased rate.1
Most elderly individuals show decreased engage-
Age-associated cognitive and ment, risk-taking, and goal-oriented behaviors, and
behavioral changes become more conventional, cautious, and routine-
bound, which is generally attributed to changes in
The most consistent behavioral change in the elderly frontal lobe executive functions. Reasoning about
observed in neuropsychologic studies is a general familiar material holds up well with aging. In con-
slowing of mental processing. Some studies have trast, when reasoning is brought to solving unfa-
even suggested that psychomotor slowing and slowed miliar or complex problems, and to those requiring
cognitive processing can account for most of the the subject to distinguish relevant from irrelevant
aging-associated performance decline. Further or redundant elements, then older persons tend to
analyses of performance slowing in the elderly have do increasingly poor with advancing age. Concept
indicated that the slowing tends to occur at decision formation and abstraction also suffer with aging, as
points. An increased cautiousness of many elderly older persons tend to think in more concrete terms.
persons may also add to their slow performance. The Mental flexibility for making new abstractions and
intelligence quotient (IQ) test in the elderly usually forming new conceptual links diminishes with age,

31
Other documents randomly have
different content
guide will be necessary, and Davis, of Jackson, is a good one. From
Jefferson and Randolph the upper waters of the Moose, and Israel’s River
(especially in the Mount Jefferson ravine), are fished with good success. E.
A. Crawford, of East Jefferson, knows the best spots. From Bartlett there
should be good fishing on Sawyer’s River, above the Livermore mills.
Consult Frank George, the veteran landlord of the Bartlett House. From
Crawford’s the best fishing-ground is Ethan’s Pond, behind Mount Willey.
At Franconia the writer has seen some fine strings brought from the
Copper-mine Brook (back of Mount Kinsman). Fair fishing may also be had
on Lafayette Brook—ask Charles Edson, of the Edson House. Profile Lake
is stocked with trout for the benefit of guests of the hotel. The upper
streams of the Pemigewasset are all good fishing-ground. Apply to Mr. D. P.
Pollard, North Woodstock, or Merrill Greeley, Waterville. The houses of
both are resorted to by experienced fishermen who track the East Branch or
Mad River tributaries. Pickerel and bass are caught in Lakes
Winnipiseogee, Squam, Chocorua, Ossipee, and Silver, besides scores of
ponds lying chiefly in the lake region.
N.B.—Those going exclusively to fish should go early in the season for
the best sport.
Guides.—The landlords will either accompany you or procure a suitable
person.
Camping Out.—A wall tent is preferable, but two persons get along
comfortably in one of the “A” pattern. Get one with the fly, which can be
spread behind the tent, thus giving an additional room, in which the cooking
and eating may be done under cover. Set up your tent where there is natural
drainage—where the surface water will run off during wet weather. Dig a
shallow trench around it, on the outside, for this purpose, and if you can
obtain them, lay boards for a floor. A kerosene-oil stove, with its utensils,
folding cot-bed, camp-chairs, and mess-chest, containing dishes (tin is
best), constitute a complete outfit, to be reduced according to convenience
or pleasure. To make a woods-man’s camp, first set up two crotched posts
five feet high, and six or eight apart (according to number). On these lay a
pole. From this pole three or four others extend to the ground. Then cut
brush or bark for the roof and sides, and build your fire in front. For a camp
of this sort a hatchet and packet of matches only are necessary. But always
pitch your encampment in the vicinity of wood and water.
 Mount Washington Railway.—Length, from base to summit, 3 miles.
Rise in the three miles, 3,625 feet. Steepest grade, 13½ inches in three feet,
or 1980 feet to the mile. Begun in 1866; completed in 1869.
Mount Washington Carriage-road.—Length, 8 miles. Average grade,
one foot in eight. Steepest grade, one foot in six. Begun in 1855; finished in
1861.
Mount Washington Signal Station.—The Summit was first occupied for
scientific purposes in the winter of 1870-’71. Since then it has been
attached to the Weather Bureau at Washington, and occupied by men
detailed from the United States Signal Corps, the men volunteering for the
service.
ALTITUDES.—The following list of altitudes of the more important and
well-known points has been compiled from the publications of the
Geological Survey of New Hampshire and of the Appalachian Mountain
Club. The figures in heavy-face type are the results either of actual
levelling or of trigonometrical survey, while the remainder depend upon
barometrical measurement. Where the mean of two not widely-differing
authorities is given, the fact is denoted by the letter “m” preceding the
figures:
MOUNTAIN SUMMITS.
Adams m 5785
Ascutney (Vermont) 3186
Black (Sandwich Dome) 3999
Boott’s Spur 5524
Cannon 3850
Carrigain m 4651
Carter Dome m 4827
Chocorua 3540
Clay 5553
Clinton m 4315
Crawford 3134
Giant’s Stairs 3500
Gunstock 2394
Iron about 2000
Jefferson 5714
Kearsarge, S. (Merrimack County) 2943
Kearsarge, N. (Carroll County) 3251
Lafayette 5259
Madison m 5350
Moat (North peak) 3200
Monadnock m 3177
Monroe m 5375
Moosilauke 4811
Moriah 4653
Osceola m 4408
Passaconnaway 4200
Percy (North peak) 3336
Pleasant (Great range) m 4768
Pleasant (Maine) 2021
Starr King m 3872
Twin about 5000
Washington 6293
Webster 4000
Whiteface 4007
Willey 4300
VILLAGES AND HOTELS.
Bartlett (Upper) 660
Bethlehem (Sinclair House) m 1454
Franconia 921
Crawford House 1899
Fabyan “ 1571
Flume “ 1431
Glen “ 1632
Gorham 812
Jackson 759
Jefferson Hill 1440
Jefferson Highlands (Mt. Adams House) 1648
Lancaster 870
North Conway 521
 Plymouth 473
Profile House 1974
Sugar Hill (Post Office) 1351
Waterville (Greeley’s Hotel) m 1544
Willey House 1323
NOTCHES.
Carter Notch 3240
Cherry Mt. Road (summit) m 2180
Crawford or White Mt. Notch 1914
Dixville Notch 1831
Franconia Notch m 2015
Pinkham Notch (south of Glen House) 2018
Carrigain Notch 2465
MISCELLANEOUS.
Ammonoosuc Sta. (base of Mt. Washington) 2668
Camp of Appalachian Mountain Club, on the Mt. Adams path 3307
Echo Lake (Franconia) m 1928
Lake of the Clouds 5053
Lake Winnipiseogee 500
Distant Points Visible from Mount Washington (taken from
“Appalachia”).—Mount Megantic (Canada), 86 miles, seen between
Jefferson and Adams; Mount Carmel, 65 miles, just over Mount Adams;
Saddleback, 60 miles, head of Rangely Lakes; Mount Abraham, 68 miles,
N., 47° E.; Ebene Mountain, 135 miles, vicinity of Moosehead Lake (rarely
seen, even with a telescope); Mount Blue, 57 miles, near Farmington, Me.;
Sebago Lake, 43 miles, over Mount Doublehead; Portland, 67 miles, over
Lake Sebago; Mount Agamenticus, 79 miles, between Kearsarge and Moat
Mountains; Isles of Shoals, 96 miles, to the right of Agamenticus (rarely
seen); Mount Monadnock, 104 miles, between Carrigain and Sandwich
Dome; Mount Ascutney (Vt.), 81 miles, S., 45° W.; Killington Peaks (near
Rutland, Vt.), 88 miles, on the horizon between Moosilauk and Lincoln;
Camel’s Hump (Vt), 78 miles, over Bethlehem Street; Mount Whiteface
(Adirondack chain, N.Y.), 130 miles, over the right slope of Camel’s Hump;
Mount Mansfield (highest of Green Mountains), 77 miles, between Twin
Mountain House and Mount Deception; Mount Wachusett (Mass.), 126
miles, is also visible under favorable conditions, just to the right of
Whiteface (N. H.).
MOUNTAIN PATHS. [Those with an asterisk (*) were built by the
Appalachian Mountain Club.] Chocorua.—There are three or four paths.
The best leads from the Hammond Farm, 2½ miles from the Chocorua Lake
House, and 14 miles from North Conway. The ascent, as far as the foot of
the final peak, is feasible for ladies. From this point the easiest way is to
flank the peak to the left until an old watercourse is reached, which may be
followed nearly to the summit.
*Moat.—An old path leads from the Swift River road to the summit of
the South Peak. Another, from the clearings on an old road which extends
along the base of the South Peak, leads to the top of the middle ridge; but
the best path for tourists is the one from Diana’s Baths, on Cedar Brook,
following the stream to the foot of the ridge, thence over the ridge to the
summit of the North Peak. Path well made, and plainly marked with signs
and cairns; about 3½ miles in length.
*Middle Mountain, North Conway.—Beginning at the ice-ponds near
Artists’ Falls House, the path extends around the base of Peaked Mountain,
thence to the bare ledges which reach to the summit. Distance, 1⅝ miles.
Path well marked, and the view very beautiful.
Kearsarge, North Conway.—A bridle-path starts from a farm-house near
Kearsarge Village, and extends to the summit. Distance, nearly 3 miles.
Route plain, and not difficult.
*Mount Bartlett.—The path starts near the Pequawket House, Lower
Bartlett, follows old logging roads for some distance, runs thence directly to
the summit. From the summit the path extends along the ridge until it joins
the bridle-path to Kearsarge.
*Carrigain.—The route leads from the mills at Livermore, which are
reached by a road leaving the P. & O. R.R. at Livermore Station. From the
mills, logging roads are followed—crossing Duck Pond and Carrigain
Brooks—to the base; thence by a plain path through a fine forest to “Burnt
Hat Ridge,” from which it is only a short distance to the summit.
From mills to summit is about 5 miles. Station to mills, 2 miles.
*Livermore-Waterville Path.—This is intended for a bridle-path. Starting
from the mills at Livermore, a logging-road is followed nearly two miles on
the southerly side of Sawyer’s River. Here the path begins and runs along
the north-west base of Green’s Cliff, crosses Swift River at a beautiful fall,
thence through the Notch south of Mount Kancamagus to Greeley’s, in
Waterville. The path is well marked by painted signs. Distance from
Livermore to Swift River, 5 miles; to Greeley’s, 12 miles.
*Mount Willey.—Path leaves the P. & O. R.R. a little south of Willey
Station. The rise is rapid until the Brook Kedron is reached; this brook is
then followed to its source, thence the path leads direct to the summit.
Distance, 1½ miles. The climb is steep; but the view unsurpassed.
Crawford Bridle-path leads from the Crawford House to the summit of
Washington. Path is plain, and the travelling along the ridge is easy; but it is
not in condition for horses. See pp. 325, 326.
*Carter Notch.—Path begins near the end of the Wildcat Valley road,
about 5½ miles from Jackson; thence it follows the valley of the brook to
the ponds in the Notch. From the ponds it follows Nineteen Mile Brook to
the clearing back of the Glen House. The travelling is easy; the view in the
Notch grand.
Distance from the road to the ponds, about 4 miles; from the ponds to the
Glen House, about the same.
*Carter Dome.—The path starts from the larger pond in the Notch, and
is well marked to the summit. It is very steep, and about 1½ miles in length.
Great Gulf.—A path beginning near the Glen House goes through this
gorge. From the end of the path the carriage-road or railroad on Mount
Washington may be reached by a severe climb up the side of the ravine.
Tuckerman’s Ravine.—The Glen House path leaves the Mount
Washington carriage-road about 2 miles up, then crosses through the forest
to Hermit Lake.
*Via Crystal Cascade.—The Mountain Club path begins about 3 miles
from the Glen House, on the Jackson road, ascending the stream until it
joins the Glen House path near Hermit Lake. Here the Club has a good
camp for the use of travellers. Beyond, a single path extends to the Snow-
field; and a feasible route has been marked with white paint on the rocks—
up the head wall of the ravine, and thence to the summit.
*Mount Adams.—This path starts opposite the residence of Charles E.
Lowe, on the road from Jefferson Hill to Gorham, about 8½ miles from
either town, and climbs the steep spur forming one wall of King’s Ravine,
following over the ledges to the westerly peak, thence to the summit.
Distance, about 4 miles. Nearly half way up the spur a good camp has been
built for the use of climbers. The way over the ledges is marked by cairns.
Mount Jefferson may be reached by turning to the right before reaching the
summit of the westerly peak; Madison by turning to the left.
*King’s Ravine.—The path branches from the Mount Adams path about
1½ miles from Lowe’s. The bowlders in the Ravine are reached without
great difficulty. From the bowlders up the head-wall, and through the gate-
way, the climb is arduous; and the way is not very distinctly marked. From
the gate-way, Madison and the several peaks of Adams may be reached.
Mount Madison.—There are several routes up Madison, but the best is
probably that leading up the ridge from “Dolly” Copp’s, on the Old
Pinkham Road. The climb is tedious, and the path somewhat overgrown.
The Mountain Club will probably clear and keep this path in good
condition.
*Bridal Veil Falls.—Path starts from Horace Brooks’s, on the road from
Franconia to Easton—2 to 3 miles from Sugar Hill and Franconia Village. It
follows an old road across the clearings to Copper-mine Brook, thence by
the brook to the foot of the Falls. Distance, 2½ miles from Brooks’s.
Walking easy.
The path to the Flume on Mount Kinsman leads from the same highway
about a mile beyond Brooks’s.
Mount Lafayette.—The bridle-path begins near the Profile House,
turning Eagle Cliff, and crossing over to the main ridge. It leads nearly to
the summit of the ridge, thence across the col by the lakes, and up the main
peak. Distance, 3½ to 3¾ miles.
Mount Cannon.—The path enters the forest near the cottages in front of
the Profile House. The summit is reached by a steep climb of 1½ miles. The
Cannon Rock is a short distance down the mountain-side, to the left of the
path as it emerges from the forest; the forehead rock of the Profile can be
reached by bearing down the mountain diagonally to the right from Cannon
Rock until the edge of the cliff is reached. It is a hard scramble to the latter.
Black Mountain, Waterville.—The new path leaves the highway 2 miles
below Greeley’s, near Drake’s Brook. It runs near the edge of the ravine of
Drake’s Brook, crosses the ridge between Noon and Jennings’ Peaks—to
each of which a branch path leads—thence up the northerly slope of the
main summit. Distance from the road to the summit is 3¼ miles. The views
are very fine, and the climb easy for ordinary walkers.
Osceola.—Path leaves the Greeley-pond path beyond the saw-mill above
Greeley’s, bearing to the left. Ascent easy. Distance, about 4 miles.
Tecumseh.—Path branches from the Osceola path at the crossing of the
west branch of Mad River, ⅞ of a mile from Greeley’s. The grade is easy,
except for a short distance near the summit. Distance from Greeley’s, 3
miles.
Tri-Pyramid.—The great slide on Tri-Pyramid may be reached from
Greeley’s by a path across the pasture to the right from the rear of the
house, thence about 1½ miles through fine old woods to a deserted clearing
known as Beckytown. From here the stream may be followed by
clambering over the débris of the slide nearly 2 miles to the base of the
South Peak. The summit is reached by climbing to the apex of the slide,
thence bearing up to the right a short distance through low woods.
*Thornton-Warren Path.—This path was built to enable visitors in the
Upper Pemigewasset Valley or in Warren to cross from one locality to the
other, avoiding the long détour via Plymouth. It starts from the Profile
House stage-road at the junction of the Tannery road, in West Thornton,
crosses Hubbard Brook at this point, and passes over a long stretch of
pasture until the woods are reached. At this point, and at all doubtful points,
signs have been placed. For much of the distance the path follows Hubbard
Brook, and passes out through the Notch between Mounts Kineo and
Cushman to an old road-way leading to clearings on Baker’s River, near the
mountain-houses at the foot of Mount Moosilauke.
Distance from the stage-road to the road-way in Warren, 8 miles. A
permanent camp has been built half-way on Hubbard Brook.
A trail has been spotted from a point in the path about 1 mile north of the
camp to the summit of Kineo.

INDEX.
 Refer to a mountain, lake, or river, under its proper name, thus: Washington (Mount);
Squam (Lake); Saco (River).
The abbreviations in parentheses show that the town or village is on the line of a
railway: (E. R.R.) stands for Eastern; (P. & O.), Portland and Ogdensburg; (B., C., & M.),
Boston, Concord, and Montreal; (G. T. R.), Grand Trunk; (Pass.), Passumpsic.

A, B, C, D, E, F, G, H, I, J, K, L, M, N, O, P, R, S, T, V, W.
Adams, Mount, from North Conway, 55;
from Thorn Hill, 122;
from Wildcat Valley, 133;
from Carter Dome, 142;
from the Glen House, 145;
from Mount Washington carriage-road, 181;
ascent by King’s Ravine, 298;
ascent from Mount Washington, 312-315;
the apex, 315;
view from, 316.
Adirondacks, from Moosehillock, 273.
Agassiz, Mount, from Profile House Road, 249, 276.
Agiochook, or Agiockochook (Indian name for the White Mountains), 120.
Amherst, Sir Jeffrey (Gen.), in the French War, 259.
Ammonoosuc, Falls of, 304.
Ammonoosuc River, source of, 179.
Ammonoosuc Valley, from Mount Clinton, 98;
at Bethlehem, 277;
at Fabyan’s, 300.
Androscoggin River, at Gorham, 170;
at Berlin, 174;
at Shelburne, 176;
at Bethel, 177.
Appalachian Mountain Club, 62, 221.
Artists’ Falls (North Conway), 46, 47.
Autumn foliage, 66, 67.

Baker’s River (branch of Pemigewasset, branch of the Merrimack), 210;

falls on, 269.
Bald Mountain, an inferior summit of Chocorua, 26.
Ball, B. L., lost on Mount Washington, 186.
Bartlett Bowlder, 58.
Bartlett (P. & O. R.R.), mountains surrounding, 61, 62;
ascent of Mount Carrigain from, 62-65.
Basin (Franconia Pass), 231.
Beecher’s Cascade (near Crawford House), 89.
Belknap, Jeremy, D.D. (historian of New Hampshire), quoted, 69.
Belknap, Mount (Lake Winnipiseogee), 8.
Bemis, Dr. Samuel A., home of, 69, 70.
Berlin (G. T. R.), 172;
the Falls, 174, 175.
Bethel, Maine (G. T. R.), 177.
Bethlehem (B., C., & M. R.R.), 276;
admirable position of as a centre, 277;
Bethlehem Street, 278, 279;
fine views from, 280, 281;
a sunset from the “Maplewood,” 282-284;
White Mountains from, 284;
the Hermit, 286;
the peddler, 288.
Bigelow’s Lawn (Mount Washington), 198.
Black Mountain (Sandwich Dome), from West Campton, 216;
Noon Peak, 220;
from Waterville (Greeley’s), 221.
Boott’s Spur (Mount Washington), 146;
from the plateau, 198.
Bourne, Lizzie, death of, on Mount Washington, 310.
Bridal Veil Falls (Mount Kinsman), 255.
Brown, George L. (painter), referred to, 253.
Buck-board wagon described, 273.

Campton, 211;
Campton Hollow, 214;
West Campton, and view from, 215;
Sanborn’s, 216;
annals of Campton, 216.
Campton Village (Pemigewasset Valley), 218.
Cannon (or Profile) Mountain, from West Campton, 215;
from the clearing below the Profile, 231;
remarkable profile on, 232;
from Franconia, 252.
Carrigain, Mount, from Chocorua, 30;
from Bartlett, 62;
ascent from Bartlett, 62-64;
view from summit, 64, 65.
Carrigain Notch, from Mount Chocorua, 30;
from Mount Carrigain, 64.
Carter Dome, 133;
the Pulpit, 136;
ascent of, and view from, 140, 141.
Carter Mountains, from Gorham, 170.
Carter Notch, from Chocorua, 31;
from North Conway, 40;
from Thorn Hill, 122, 132;
way into, from Jackson, 132;
impressive desolation of the interior, 137;
the Giants’ Barricade, 137, 138;
the lakes, 139;
way out to Glen House, 143.
Castellated Ridge (Mount Jefferson), 314.
Cathedral (North Conway), 46.
Cathedral Ledge (North Conway), 41, 42.
Cathedral Woods (North Conway), 55.
Centre Harbor, approach to, by Lake Winnipiseogee, 8-10;
settled, 10;
route by stage to West Ossipee via Sandwich and Tamworth, 18-21.
Chandler, Benjamin, lost on Mount Washington, 186.
Cherry Mountain (Valley of Israel’s River), 291;
Owl’s Head, 292;
road to Fabyan’s, 300.
Chocorua, Lake, from the mountain, 29, 31, 32.
Chocorua (Sho’kor’ua), Mount, from Lake Winnipiseogee, 9;
from Red Hill, 16;
legend of, 21;
 ascent from Tamworth, 25-28;
landscapes from, 29-31;
from Mount Willard, 92.
Clay, Mount (next north of Washington), 169;
ascent of, 312.
Clinton, Mount (near Crawford House), 97;
view from summit, 100. (First mountain ascended by Crawford Path.)
Connecticut Ox-Bow, 256-258.
Conway, or Conway Corner (E. R.R.), superb view of the great chain from,
33.
Copp Farm (view-point for seeing “The Imp”), 165.
Copp, Nathaniel, his adventurous deer-hunt, 167.
Copper-mine Brook (branch of Gale River), 255.
Crawford, Abel, described, 70-72.
Crawford, Ethan Allen, 71, 72;
his burial-place, 302.
Crawford bridle-path, opened, 89;
march to the summit (see Chapter X.);
Mount Clinton first, 117;
the crystal forests, 98;
Liliputian wood, 99;
fine view from summit, 100;
frost-work, 100;
Mount Pleasant next, 102;
in a snow-storm, 102;
crossing the ridge, 103;
Oakes’s Gulf, 103;
Mount Franklin next, 103;
(water here) weird objects by the way, 104;
Mount Monroe next (two peaks, with shallow ponds near the path);
the plateau, 105;
base of the cone reached, 105;
ascent of the cone, 107;
the stone corral, 107;
the summit, 108.
Crawford Glen (Saco Valley), 69.
Crawford House (summit of Crawford Notch), its surroundings, 87-94.
Crawford, Mount (Saco Valley, east side), 69;
Davis Path to Mount Washington, 73;
view of from Frankenstein Bridge, 74.
Crawford Notch (see Great Notch of the White Mountains).
Crawford, T. J., opens a bridle-path to the summit, 89.
Crystal Cascade (Pinkham Notch), 149, 150.

Dartmouth, see Jefferson.

Davis Path (to Mount Washington), 73;
junction with Crawford Path, 198.
Deception, Mount (near Fabyan’s), 300.
Destruction of mountain forests, 172.
Devil’s Den (North Conway), 45, 46.
Diana’s Baths (North Conway ), 46.
Douglass, William, M.D., quoted, on the origin of the name White
Mountains, 121, note.
Dwight, Timothy, L.L.D., 71 (see his “Travels in New England,” and
journeys through the mountains).

Eagle Cliff (Franconia Pass), from Flume House, 225;

from Profile House, 238, 239;
ascent by the bridle-path, 243;
from Franconia, 254.
Eagle Lakes (Mount Lafayette), 244. (Also called Cloud Lakes.)
Eagle Mountain (Eagle Mountain House), Wildcat Valley, Jackson, 133.
Early settlements by white people, 216, 217, 293.
Echo Lake (Franconia Pass), 239.
Echo Lake (North Conway), 45.
Elephant’s Head (Crawford Notch), 87.
Ellis River (branch of the Saco; rises in Pinkham Notch), see Goodrich
Falls, 125;
Glen Ellis Falls, 151;
incident connected with, 153.
Emerald Pool (near Glen House, Pinkham Notch), 147, 148.
Endicott Rock, a surveyor’s monument at the outlet of Lake Winnipiseogee,
10.
Fabyan’s (B., C., & M. and P. & O. R.R.), view at, 300;
Mount Washington Railway, 301;
Eleazer Rosebrook and E. A. Crawford, 302, 303.
Fall of a Thousand Streams, 162.
Farmer, John (historian), quoted, 210.
Field, Darby, makes the first ascent of Mount Washington, 116-119;
second ascent, 119, see note.
Flume (Franconia Pass), way to and description of, 226-228.
Flume Cascade, see description by Dr. T. Dwight, in his “Travels in New
England.”
Flume House (Franconia Pass), 224.
Franconia Mountains, from West Campton, 215;
from Bethlehem, 280;
from Jefferson, 292.
Franconia Pass (Chapters II. and III., Third Journey), Flume House, 224;
the Pool, 225;
the Flume, 226;
the Basin, 231;
Mounts Cannon and Lafayette, 231, 232;
the “Old Man,” 232;
Profile Lake, 232;
Profile House, 237;
Eagle Cliff, 238;
Echo Lake, 239;
sunset in the pass, 240;
from Bethlehem heights, 279.
Franconia village (Iron Works), from Mount Lafayette, 243;
general view of, 251;
fine views in, 253, 254.
Frankenstein Cliff (Saco Valley), named, 73;
appearance of, from the valley, 73, 74;
the bridge, 74.
Fryeburg, Maine (P. & O. R.R.), 33-38.

Gale River (branch of the Ammonoosuc, branch of the Connecticut), 243.

Garfield, Mount (see Haystack), 284.
Giant’s Stairs (Saco Valley, east side), 73;
 from Jackson, 123, 129.
Gibbs’s Falls (near Crawford House), 97.
Glen Ellis Falls, 151, 152; legend of, 152.
Glen House, way to, by Jackson and Carter Notch, 131;
its surroundings, 144;
carriage-road to the summit, 144;
Mount Washington from, 144, 145;
Emerald Pool, 147, 148;
Thompson’s Falls, 146;
Crystal Cascade, 149;
Glen Ellis Falls, 151;
Tuckerman’s Ravine, 155;
The Imp, 165;
to or from Gorham, 165, 170;
from Mount Washington carriage-road, 181.
Goodenow’s, see Sugar Hill.
Goodrich Falls (Ellis River), 125.
Gorham (G. T. R.), its situation, 169.
Grand Monadnock, from Red Hill, 17;
from Mount Washington, 192.
Great Gulf, from Glen House, 165;
from Mount Washington carriage-road, 181, 185;
from Mount Clay, 313.
Great Notch of the White Mountains (Crawford Notch), from Mount
Chocorua, 31;
from Mount Carrigain, 64, 65;
approach to, by the Saco Valley, 76;
the mountains forming it, 77;
Willey, or Notch House, 77;
landslip of 1826, 79, 80;
the Cascades, 84, 85, 89, 97;
Gate of the Notch, 86;
summit of the Notch (Crawford House), 86;
Elephant’s Head, 87;
discovery of the Pass, 88, 89;
the Notch from Mount Willard, 91;
from Mount Clinton, 100.
Greeley’s, see Waterville.
Green Mountains, from Mount Washington, 190;
from Moosehillock, 273.
Gyles, John (Capt.), quoted on the Indian name for the White Mountains,
120.

Hancock, Mount, from the Ellsworth road (Campton), 216;

from Moosehillock, 272.
Hart’s Ledge (Saco Valley, east side, near Bartlett), 62.
Haverhill (B., C., & M. R.R.), 257.
Hawthorne, Nathaniel, origin of his story of “The Great Carbuncle,” 119;
death of, 209;
legend of “The Great Stone Face,” 235.
Hayes, Mount (Gorham, New Hampshire), 169-171.
Haystack, Mount (now Mount Garfield), 254.
Hermit Lake (Tuckerman’s Ravine, Mount Washington), 159.
Hitchcock, C. H. (geologist), 197.
Humphrey’s Ledge (near Glen Station), 41.
Hunter, Harry W., lost on Mount Washington, 199, note.
Huntington’s Ravine, from Carter Dome, 142.

Idlewild (near Crawford House), 89.

Imp, The (rock profile near Glen House), 166.
Indians, customs of mountain tribes, 10;
Sokokis, or Pigwackets, or Pequawkets, destruction of by Love-well, 34-
38;
Indian names, 24, 25, note;
superstitions regarding the high summits, traditions, etc. (see Chapter I.,
Second Journey);
attack Shelburne, 177;
at Plymouth, 210;
attack Dartmouth (Jefferson), 294.
Intervale (North Conway, E. R.R. and P. & O. R.R.), superb panorama
from, 55-57;
see art. North Conway.
Israel’s River (branch of the Connecticut), 291.
Jackson (see Chapters II. and III., Second Journey), 122-143;
how to get there from North Conway, 122;
its topography, 123;
Jackson Falls (on Wildcat River), 124;
Fernald’s Farm, 130;
Wildcat Valley, 133;
to Carter Notch, 133-140.
Jackson, C. T. (geologist), quoted, 197, note.
Jackson Falls (Wildcat River), 124.
Jefferson, Mount, from Jefferson Hill, 293;
Ravine of the Cascades, 297;
ascent from Mount Washington, 312;
Ravine of the Castles, 313;
Castellated Ridge, 314.
Jefferson (branch R.R. from Whitefield), 291;
Jefferson Hill, 292;
antecedents of, 293;
Indian attack on, 294;
East Jefferson, 295;
to Randolph Hill, 297;
to Fabyan’s, 300.
Jockey Cap (Fryeburg, Maine), 34.
Josselyn, John (author of “New England’s Rarities”), ascends Mount
Washington, 119.

Kearsarge, Mount, from North Conway, 39, 40, 41;

winter ascent of, 47-54;
view from summit, 51, 52;
from Bartlett, 62;
from Carter Dome, 141.
King, Thomas Starr, tribute to, 294, 295.
King’s Ravine (Mount Adams), from Randolph Hill, 298;
from Mount Adams, 317.
Kinsman, Mount (next south of Cannon, Franconia group), 244, 252.

Lafayette, Mount, from West Campton, 215;

see Chapter III., Third Journey;
 Eagle Cliff, 238, 239;
from Echo Lake, 240;
ascent from the Profile House, 243-247;
the Notch, 243;
the ravines, 243-254;
Eagle Lakes, 244;
summit and view, 246, 247;
from Franconia Iron Works, 252;
from Newbury, Vermont, 258;
from Bethlehem heights, 279.
Lake of the Clouds (Mount Washington), 198.
Lary’s (Gorham, New Hampshire), 171.
Lead Mine Bridge (Shelburne, G. T. R.), grand view from, 175, 176.
Legends of General Hampton and the Devil, 11-14;
of Mount Chocorua, 21-24;
of Passaconnaway, 24, 25, note;
Indian tradition of the Deluge, 114;
the Indian’s heaven, 115;
the Great Carbuncle, 115;
the war party and its prisoners, 127, 128;
the youthful lovers, 128;
of Glen Ellis Falls, 152;
of the Silver Image, 263.
Lion’s Head (Tuckerman’s Ravine), 142, 146, 159.
Lisbon (B., C., & M. R.R.), discovery of gold ores in, 251.
Littleton (B., C., & M. R.R.), from Bethlehem, 279.
Livermore (P. & O. R.R.), Saco Valley, logging hamlet of, 63;
way to the Pemigewasset, 221.
Livermore Falls (Pemigewasset River), 212.
Logging on the Androscoggin, 173, 174.
Lonesome Lake (Mount Kinsman), 244.
Long Island, Lake Winnipiseogee, east shore, 9.
Lovewell, John (captain of colonial rangers), battle with the Sokokis, 34-38.
Lovewell’s Pond (scene of Lovewell’s fight), 34.
Lowell, Mount (Saco Valley), slide on, 64.

Mad River and Valley (branch of Pemigewasset), 218.

Madison, Mount (next north of Adams), 165.
Marsh, Sylvester, projector of Mount Washington railway, 301.
Merrimack River, source of, 65.
Moat Range, position of, 39;
cliffs of, 40, 41, 44;
the ascent, 47;
from Jackson Falls, 124.
Monroe, Mount, from Tuckerman’s Ravine, 160.
Moose River (branch of Androscoggin), 171.
Moosehillock, or Moosilauke, from Lake Winnipiseogee, 10;
from Chocorua, 30;
from Pemigewasset Valley, 223;
from Newbury, Vermont, 258;
see Chapter VII., Third Journey, 269-275;
how to reach the mountain, 269;
the mountain’s top, 271;
view from, 273;
from Bethlehem, 279.
Moriah, Mount (Carter Chain, near Gorham), 169.
Mountain Butterfly, 202.

Nancy’s Brook (Saco Valley), story of, 67-69.

Newbury, Vermont (Pass. R.R.), 257.
Nineteen Mile Brook (branch of the Peabody River, a branch of the
Androscoggin; rises in Carter Notch), 143.
North Conway (E. R.R. and P. & O. R.R.), topographical features of, 39-41;
excursions from, 57;
see Intervale, White Horse Ledge, Cathedral Ledge, Humphrey’s Ledge,
Echo Lake, Diana’s Baths, Artists’ Falls, Kearsarge and Moat Mountains,
etc.

Oake’s Gulf (in great range), 103.

Old Man of the Mountain (Franconia Pass), 231-236;
legends of, 235.
Ossipee Mountains, from Lake Winnipiseogee, 8.
Owl’s Head (Lake Memphremagog), from Moosehillock, 273;
Cherry Mountain, 292.
Peabody River (branch of the Androscoggin; rises in Pinkham Notch), 144,
154, note.
Pemigewasset River, branch of Merrimack, 210;
Livermore Falls, 211;
East Branch, 223.
Pemigewasset, Mount (near Flume House), ascent and view, 229.
Pemigewasset Valley (Chapter I., Third Journey), 210-223;
villages of, 212.
Pemigewasset Wilderness, way through, 221, 229.
Percy Peaks, 280, note.
Perkins Notch, position of, 133.
Pilot Mountains from Gorham, 170;
origin of name, 170, 171.
Pine Mountain (Gorham, New Hampshire), 170.
Pinkham Notch from Thorn Hill, 122;
from the road between Jackson and Glen House, 129;
from Glen House, 144;
see Thompson’s Falls, Emerald Pool, Crystal Cascade, Tuckerman’s
Ravine, Glen Ellis Falls, etc., 144-164.
Pleasant, Mount, from Fabyan’s, 300.
Plymouth (B., C., & M. R.R.), 209;
routes through the mountains, 211.
Pool, The (Franconia Pass), 225.
Portland and Ogdensburg Railroad, passage of the White Mountains Notch,
93.
Prime, W. C., referred to, 244.
Profile House (Franconia Pass), its attractions, 237-240;
see Old Man, Profile Lake, Mounts Cannon and Lafayette, Eagle Cliff,
Echo Lake, etc.;
to Bethlehem by the old highway via Franconia, 248;
by rail, 248.
Profile Lake (Franconia Pass), 232.
Prospect, Mount (Holderness), 214.

Randolph Hill, drive to, and view from, 297, 298.

Ravine of the Castles (Mount Jefferson), 313.
Raymond’s Cataract, from Carter Dome, 142;
from Pinkham Notch, 147;
see Tuckerman’s Ravine.
Red Hill from Lake Winnipiseogee, 10;
ascent of, from Centre Harbor, and view from summit, 14-17.
Ripley Falls (on Cow Brook, Saco Valley), 89.
Rogers’s, Robert (Major), account of the White Mountains, 119, 121, note;
destroys St. Francis, 259;
see Chapter VI., Third Journey.
Rosebrook, Eleazer, sketch of, 302, 303.

Saco Valley (Chapters IV. to IX., inclusive), from Mount Chocorua, 31;
at Fryeburg (Maine), 33;
at North Conway, 39;
at Bartlett, 61-65;
from Mount Carrigain, 64, 65;
source of the Saco, 88;
historical incident, 153.
Sandwich Mountains from Lake Winnipiseogee, 8;
from Sandwich Centre, 19;
from Tamworth (Nickerson’s), 24.
Sandwich (town of), mountains near, 19.
Sandwich Notch, position of, 218.
Sawyer’s River (branch of the Saco), valley of, 62, 63.
Sawyer’s Rock (Saco Valley, west side, near Bartlett), 62.
Schoolcraft, Henry Rowe, quoted on the Indian name for the White
Mountains, 120.
Silver Cascade (Crawford Notch), 85.
Snow Arch (Tuckerman’s Ravine), 161, 162.
Spencer, Jabez (General), settles Campton, 216.
Squam Lake from Red Hill, 16.
St. Francis de Sales, sacked by Rogers, 259;
see Chapter VI., Third Journey.
Star Lake (Mount Adams), 317.
Stark, John (General), captured by Indians, 210, 211.
Stark, William, 210, 211.
Starr King Mountain, 291.
Storm Lake (between Madison and Adams), 317.
Sugar Hill, from Profile House road, 249;
view from, 252, 253.
Sullivan, James (Governor of Massachusetts), his authority for the story of
“The Great Carbuncle,” 116;
quoted, 153.
Swift River (branch of the Saco), from Mount Chocorua, 30.

Tamworth Iron Works (point from which Chocorua is usually ascended),

21, 25.
Thompson’s Falls (near Glen House), 146.
Thorn Mountain, from North Conway, 40;
walk over Thorn Hill (lower spur of Thorn Mountain) to Jackson, 122,
132.
Tripyramid Mountain, from Mad River Valley, 219;
slide on, 221.
Trout-breeding, State establishment at Plymouth, 212.
Trout-fishing begins in New Hampshire May 1, 213.
Trumbull, J. Hammond, LL.D., quoted on the Indian names for the White
Mountains, 120, note.
Tuckerman’s Ravine from Mount Kearsarge, 51;
from Carter Dome, 142;
from Thompson’s Falls, 146;
way into from Glen House, 156;
appearance from Glen House, 156;
Hermit Lake and Lion’s Head Crag, 159;
Snow Arch, 161;
head wall, 162;
out by the path to Crystal Cascade, 164.

Views, from Red Hill, 14-17;

from Chocorua, 29-31;
from Jockey Cap, 34;
from Conway Corner, 33;
from North Conway, 40;
from Mount Kearsarge, 51;
from the Intervale (North Conway), 55-57;
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