Aging How Science Works
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Carsten Carlberg · Stine M. Ulven · Eunike Velleuer
Aging
How Science Works
Carsten Carlberg Stine M. Ulven
Institute of Animal Reproduction and Food Department of Nutrition
Research University of Oslo
Polish Academy of Sciences Oslo, Norway
Olsztyn, Poland
Institute of Biomedicine
University of Eastern Finland
Kuopio, Finland
Eunike Velleuer
Helios Clinic
Centre for Child and Adolescent Health
Krefeld, Germany
ISBN 978-3-031-61256-5 ISBN 978-3-031-61257-2 (eBook)
https://doi.org/10.1007/978-3-031-61257-2
© The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature
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Preface
Aging is a topic that concerns everyone, since none of us can escape it. However,
aging is not a disease but resumes natural changes in physiological and biochemical
processes in the human body when we get older. We all have an individual speed of
aging, which to a large extent is related to our lifestyle and the environment we live in.
Importantly, the molecular and cellular mechanisms of aging are contained in every
of the billions of cells forming our body. Some of these cells, such as many cells of
the immune system, the skin and the intestinal tract, live only for a few days to weeks
and get life-long replaced through the actions of adult stem cells in the respective
organs. In contrast, there are cells, such as neurons and memory lymphocytes, that
can get as old as we get.
The process of aging limits the maximal life span, which is for humans in
the order of 120 years. However, so far only a very few individuals have reached
this age. How did their life differ from others that died decades earlier living in the
same environment? Is it just the absence of life-threatening diseases paired with a
healthier lifestyle? Or is this property integrated in our genome or epigenome? In this
book, we try to give answers to these questions from the perspectives of evolution,
our genome and epigenomes as well as through the functionality of our tissues and
cell types.
In order to get insight into the process of aging, we have to understand how our
body is organized and how the environment, to which we are exposed, interacts
with cellular processes, such as cellular growth, differentiation and death. Every
(human) organism represents a complex interplay between hundreds of different cell
types forming distinctive tissues and organs with specialized tasks. They need to
be highly orchestrated, especially during development, in order to keep the body
in homeostasis. Studying the cellular and molecular basis of aging is one of the
most fascinating areas in biology but also a great challenge. Nevertheless, research
made the biggest steps in elucidating biological processes via studying malfunctions
of normal mechanisms that lead to different types of syndromes and diseases, such
as premature aging syndromes and cancer.
We start this book with the describing the human genome in relation to the princi-
ples of evolution. Then, we explain the basics of gene regulation and epigenetics, i.e.,
v
vi Preface
the interplay of transcription factors and chromatin, which is the core mechanism
for the proper function of all our tissues and cell types in health, disease and aging.
Next, we shift to cellular mechanisms and discuss the impact of biochemistry and
immunity on the process of aging. In the following, the relation of aging to chronic
disorders, such as the metabolic syndrome, cancer and neurodegenerative diseases,
as well as to nutrition and physical activity is discussed. Do we get these disor-
ders because we are aging or are we aging because we get one or multiple of
these diseases? By studying premature aging syndromes we not only shed light on
biological processes but we ask ourselves what we expect from life and how we use
the time we are given. Eventually, we will have to admit that from an evolutionary
perspective aging makes sense. But what can we do to age as healthy as possible and
can we slow down the aging process by healthy diets and physical activity?
This book is linked to a series of lecture courses in “Molecular Medicine and
Genetics”, “Molecular Immunology”, “Cancer Biology” and “Nutrigenomics” that
are given by one of us (C. Carlberg) in different forms since 2002 at the University of
Eastern Finland in Kuopio. Over the last 20 years the topic of aging got more and more
important in these courses. The core of this book is related to our textbook Molecular
Medicine: How Science Works (ISBN 978-3-031-27132-8), which to a central part
is based on our book Nutrigenomics: How Science Works (ISBN 978-3-030-47663-
2). By combining basic understanding of molecular and cellular mechanism with
clinical examples, the authors hope to make this textbook a personal experience. A
glossary in the appendix will explain the major specialist’s terms.
We hope that readers will enjoy this rather visual book and get as enthusiastic
about understanding the process of aging as the authors are.
Olsztyn, Poland/Kuopio, Finland Carsten Carlberg
Oslo, Norway Stine M. Ulven
Düsseldorf, Germany Eunike Velleuer
March 2024
Contents
1 Human Genome, Development, Evolution and Aging . . . . . . . . . . . . . . 1
1.1 The Human Genome and Its Variation . . . . . . . . . . . . . . . . . . . . . . . . . 2
1.2 Principles of Development and Aging . . . . . . . . . . . . . . . . . . . . . . . . . 9
1.3 Evolutionary Perspective on Aging . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
1.4 Hallmarks of Aging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Bibiliography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
2 Principles of Gene Expression and Epigenetics . . . . . . . . . . . . . . . . . . . . 19
2.1 Gene Regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
2.2 Chromatin Structure and Epigenetics . . . . . . . . . . . . . . . . . . . . . . . . . . 22
2.3 Information Storage by Chromatin Modifications . . . . . . . . . . . . . . . 24
2.4 Epigenetics Enables Gene Expression . . . . . . . . . . . . . . . . . . . . . . . . . 33
Bibliography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
3 Epigenetics, Memory and Aging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
3.1 Transgenerational Epigenetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
3.2 Epigenetics of Aging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
3.3 Epigenetics and Time: The Circadian Clock . . . . . . . . . . . . . . . . . . . . 51
Bibliography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56
4 Biochemistry of Aging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
4.1 Principles of Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
4.2 Aging and Conserved Nutrient Sensing Pathways . . . . . . . . . . . . . . . 59
4.3 Neuroendocrine Regulation of Energy Metabolism and Aging . . . . 65
Bibliography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71
5 Molecular and Cellular Basis of Aging . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
5.1 Mitochondria and Endoplasmatic Reticulum Dysfunctions . . . . . . . 73
5.2 Apoptosis, Autophagy and the Loss of Proteostasis . . . . . . . . . . . . . . 80
5.3 Stem Cell Exhaustion and Cellular Senescence . . . . . . . . . . . . . . . . . 84
5.4 Long- and Short-Lived Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88
Bibliography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
vii
viii Contents
6 Immunity and Aging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93
6.1 Innate and Adaptive Immunity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93
6.2 Relation of Epigenetics and Immunity . . . . . . . . . . . . . . . . . . . . . . . . . 98
6.3 Inflammation and Aging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
6.4 The Aging Immune System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108
6.5 The Microbiome in Aging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112
Bibliography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116
7 Chronic Diseases and Aging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117
7.1 The Global Burden of Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117
7.2 The Metabolic Syndrome: Obesity, T2D and CVD . . . . . . . . . . . . . . 118
7.3 Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124
7.4 Neurodegenerative Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128
Bibliography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133
8 Premature Aging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135
8.1 DNA Repair Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135
8.2 Premature Aging Syndromes Associated with Genomic
Instability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139
8.3 Laminopathies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145
Bibliography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148
9 Healthy Aging and Longevity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151
9.1 Impact of Energy Balance and Dietary Macronutrient
Composition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151
9.2 Impact of Physical Activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158
9.3 Aging Clocks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160
9.4 The Socio-Economic Need of Healthy Aging . . . . . . . . . . . . . . . . . . . 163
Bibliography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167
Glossary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169
Abbreviations
1,25(OH)2 D3 1,25-dihydroxyvitamin D3
25(OH)D3 25-hydroxyvitamin D3
3D 3-dimensional
5caC 5-carboxylcytosine
5fC 5-formylcytosine
5hmC 5-hydroxymethylcytosine
5hmU 5-hydroxyuracil
5mC 5-methylcytosine
A Adenine
AC Adenylate cyclase
ACAC Acetyl-CoA carboxylase
ADP Adenosine diphosphate
AGRP Agouti-related neuropeptide
AKT AKT murine thymoma viral oncogene homolog
AMP Adenosine monophosphate
AMPK Adenosine monophosphate-activated protein kinase
AP1 Activator protein 1 (JUN-FOS heterodimer)
APC APC regulator of WNT signaling pathway
APO Apolipoprotein
AR Androgen receptor
ARC Arcuate nucleus
ARID5B AT-rich interaction domain 5B
ASC Apoptosis-associated speck-like protein containing a CARD
ATF Activating transcription factor
ATM ATM serine/threonine kinase
ATP Adenosine triphosphate
ATR ATR serine/threonine kinase
ATRX ATRX chromatin remodeler
Aβ Amyloid β
BAK BCL2 antagonist/killer 1
BANF1 BAF nuclear assembly factor 1
ix
x Abbreviations
BAX BCL2 associated X, apoptosis regulator
BCL2 BCL2 apoptosis regulator
BCL2L1 BCL2-like
BCR B cell receptor
BDNF Brain-derived neurotrophic factor
BER Base excision repair
BLM BLM RecQ like helicase
BMAL1 Basic helix-loop-helix ARNT like 1
BMF Bone marrow failure
BMI Body mass index
BRCA1 BRCA1 DNA repair associated
BRIP1 BRCA1 interacting protein C-terminal helicase 1
C Cytosine
CAMKK2 Ca2+ /calmodulin-dependent protein kinase kinase 2
CAMP Cathelicidin
CASP Caspase
CCK Cholecystokinin
CCL Chemokine C-C motif ligand
CDK Cyclin-dependent kinase
CDKN1A Cyclin-dependent kinase inhibitor 1A, also called p21
CDKN2A Cyclin-dependent kinase inhibitor 2A, also called p16
CEBP CCAAT enhancer binding protein
CFU Colony forming unit
CHEK Checkpoint kinase
CLOCK Clock circadian regulator
CNS Central nervous system
CNV Copy number variation
COPD Chronic obstructive pulmonary disease
COVID-19 Coronavirus disease 2019
CpG CpG dinucleotide
CREB3L3 cAMP responsive element binding protein 3-like 3
CRP C-reactive protein
CRTC2 CREB-regulated transcription coactivator 2
CRY1 Cryptochrome circadian clock 1
CSNK2A1 Casein kinase 2α 1
CTCF CCCTC binding factor
CVD Cardiovascular disease
CXXC1 CXXC finger protein 1
CYP27B1 Cytochrome P450 family 27 subfamily B member 1
DAF Abnormal dauer formation
DALY Disability-adjusted life-year
DAMP Damage-associated molecular pattern
DAXX Death domain associated protein
DDR DNA damage response
DEFB4 Defensin beta 4A
Abbreviations xi
DNMT DNA methyltransferase
DOHaD Developmental origins of health and disease
EGF Epidermal growth factor
EIF2AK3 Eukaryotic translation initiation factor 2α kinase 3
ENCODE Encyclopedia of DNA elements
EP300 E1A-binding protein p300, also called KAT3B
eQTL Expression quantitative trait locus
ERCC ERCC excision repair, TFIIH core complex helicase subunit
ERN1 Endoplasmic reticulum to nucleus signaling 1
ES Embryonic stem
ESR Estrogen receptor
FAS FAS cell surface death receptor
FASLG FAS ligand
FGF Fibroblast growth factor
FOXO Forkhead box O
FTO Fat mass and obesity associated
G Guanine
GABA Gamma-aminobutyric acid
Gb Giga (1000,000,000) base pairs
GH1 Growth hormone 1
GHR GH receptor
GIS1 GLG1-2 suppressor
GLP1 Glucagon-like peptide 1
GPAT Glycerol phosphate acyl transferase
GWAS Genome-wide association study
HAT Histone acetyltransferase
Hb1Ac Glycated hemoglobin
HBV Hepatitis B virus
HDAC Histone deacetylase
HDL High-density lipoprotein
HIF1 Hypoxia-inducible factor 1
HIV-1 Human immunodeficiency virus
HP1 Heterochromatin protein 1, official name CBX5
HPV Human papilloma virus
HR Homologous recombination
HSC Hematopoietic stem cell
HSF1 Heat shock transcription factor 1
HSP Heat shock protein
IgA Immunoglobulin A
IGF Insulin-like growth factor
IGF1R IGF1 receptor
IKBK Inhibitor of kappa light polypeptide gene enhancer in B cells,
kinase
IL Interleukin
ILC Innate lymphoid cell
xii Abbreviations
ILP Insulin-like peptide
indel Insertion-deletion
INF Interferon
INSR Insulin receptor
iPS Induced pluripotent stem
IRS Insulin receptor substrate
IRX Iroquois homeobox
IVF In vitro fertilization
kb Kilo (1000) base pairs
KDM Lysine demethylase
KLF4 Krüppel-like factor 4
KMT Lysine methyltransferase
LAD Lamin-associated domain
LCR Locus control region
LDL Low-density lipoprotein
LINE Long interspersed element
LKB1 Liver kinase B1
LPS Lipopolysaccharide
LTR Long terminal repeat
LXR Liver X receptor
MAF Minor allele frequency
MAPK Mitogen-activated protein kinase
Mb Mega (1000,000) base pairs
MBD Methyl-DNA-binding domain
MC4R Melanocortin 4 receptor
M-CFU Myeloid stem cells
mCH Non-CpG methylation
MCP1 Monocyte chemoattractant protein 1
MDM2 MDM2 proto-oncogene, E3 ubiquitin protein ligase
MECP2 Methyl-CpG-binding protein 2
MHC Major histocompatibility complex
miRNA Micro RNA
MLH1 MutL homolog 1
MMP Matrix metalloproteinase
MMR Mismatch repair
mRNA Messenger RNA
MSN Multicopy suppressor of SNF1 mutation
MYC MYC proto-oncogene, BHLH transcription factor
NAD Nicotinamide adenine dinucleotide
NAFLD Non-alcoholic fatty liver disease
NAMPT Nicotinamide mononucleotide phosphoribosyltransferase, also
called visfatin
NANOG Nanog homeobox
NCOR1 Nuclear receptor corepressor 1
ncRNA Non-coding RNA
Abbreviations xiii
NER Nucleotide excision repair
NFAT Nuclear factor activated T cells
NFκB Nuclear factor kappa B
NGS Next-generation sequencing
NHEJ Non-homologous end-joining
NK Natural killer
NLR NOD-like receptor
NLRP NLR protein
NPY Neuropeptide Y
NRIP1 Nuclear receptor interacting protein 1
NTS Nucleus tractor solitarius
OCT4 Octamer-binding transcription factor 4, official name POU5F1
OR Odds ratio
PALB2 Partner and localizer of BRCA2
PAMP Pathogen-associated molecular pattern
PARP1 Poly(ADP-ribose) polymerase 1
PBMC Peripheral blood mononuclear cell
PER1 Period circadian clock 1
PGC Primordial germ cell
PI3K Phosphatidylinositol-4,5-bisphosphate 3-kinase
Pol II RNA polymerase II
POMC Proopiomelanocortin
POU1F1 POU class 1 homeobox 1
PPAR Peroxisome proliferator-activated receptor
PPARGC1α Proliferator-activated receptor γ, coactivator 1A
PRC Polycomb repressive complex
PRK Protein kinase
PRKDC Protein kinase, DNA-activated, catalytic subunit
PROP1 PROP paired-like homeobox 1
PRR Pattern-recognition receptor
PTEN Phosphatase and tensin homolog
PTGS2 Prostaglandin-endoperoxide synthase 2, also known as COX2
RAPTOR Regulatory associated protein of TOR
RAS Rat sarcoma
RB1 Retinoblastoma 1
RECQL4 RecQ like helicase 4
REST RE1-silencing transcription factor
REV-ERB Reverse-Erb, official gene symbol NR1D1
RNA-seq RNA sequencing
ROR RAR-related orphan receptor
ROS Reactive oxygen species
rRNA Ribosomal RNA
S6K S6 kinase
SAM S-adenosyl-L-methionine
SARS-CoV 2 Severe acute respiratory syndrome coronavirus 2
xiv Abbreviations
SASP Senescence-associated secretory phenotype
SCFA Short chain fatty acid
SCN Suprachiasmatic nucleus
SINE Short interspersed nuclear element
SIRT Sirtuin
SNP Single nucleotide polymorphism
snRNA Small nuclear RNA
SNV Single nucleotide variant
SORT1 Sortilin 1
SOX2 SRY-box 2
SREBF1 Sterol regulatory element-binding transcription factor 1
SWI/SNF Switching/sucrose non-fermenting
T Thymine
T1D Type 1 diabetes
T2D Type 2 diabetes
T3 Triiodothyronine
TAD Topologically associated domain
TBC1D TBC1 domain family, member 1
TCGA The Cancer Genome Atlas
TCR T cell receptor
TDG Thymine-DNA glycosylase
TERC Telomerase RNA component
TERT Telomerase reverse transcriptase
TET Ten-eleven translocation
TGFβ Transforming growth factor β
TH T helper
TIFIA Transcription initiation factor IA
TLR Toll-like receptor
TNF Tumor necrosis factor
TOR(C) Target of rapamycin (complex)
TP53 Tumor protein p53
TRAF2 TNF receptor-associated factor 2
TREG Regulatory T
tRNA Transfer RNA
TSC2 Tuberous sclerosis 2
TSS Transcription start site
U Uracil
UCP Uncoupling protein
ULK1 UNC-51-like kinase 1
UTR Untranslated region
UV Ultraviolet
VDR Vitamin D receptor
VEGF Vascular epithelial growth factor
VLDL Very low-density lipoprotein
WHO World Health Organization
Abbreviations xv
WRN Werner syndrome RecQ-like helicase
XBP1 X-box-binding protein 1
ZCWPW1 Zinc finger CW-type and PWWP domain containing 1
ZMPSTE24 Zinc metallopeptidase STE24
α-MSH α-melanocyte-stimulating hormone
Chapter 1
Human Genome, Development,
Evolution and Aging
Abstract In this introductory chapter, we will briefly describe the genetic basis of
the variation of human populations and individuals, which contributes to disease
risk and speed of aging. Most recent information on human genome variations are
based on big biology consortia like the 1000 Genomes project or the UK Biobank.
Genome-wide genotyping and whole genome sequencing allow the study and anal-
ysis of complex diseases on the basis of dozens to hundreds of genetic variants, such as
single nucleotide variants (SNVs) and copy number variations (CNVs), in regulatory
and coding regions of genes. Next, we discuss the principles of (embryonic) devel-
opment and stem cells. In this context we introduce aging as the natural progressive
decline in the function of cells, tissues and organs that leads to impaired functions
of the body. Accordingly, older age is the primary risk factor for numerous non-
communicable diseases. Major hallmarks of aging are cellular senescence, genome
instability, epigenetic alterations and telomere attrition, which we discuss in more
detail in following chapters.
Keywords Human genome · Big biology projects · 1000 Genomes project · Cell
lineage commitment · Cellular reprograming · Lifespan · Healthspan ·
Senescence · Hallmarks of aging
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024 1
C. Carlberg et al., Aging, https://doi.org/10.1007/978-3-031-61257-2_1
