6.

02 Biochemistry of Aging 
Lourdes L. Balcueva, MD | April 8, 2019 
 

● Decreased ability to respond adaptively to environmental

OUTLINE  changes
I. Introduction ● Increased vulnerability to many diseases
A. Definition of Aging ● Atrophy of most organs
B. Characteristics of the Aging Process in a Medical Point of
View C. CLINICAL MANIFESTATIONS
C. Clinical Manifestations ● Hair becomes noticeable thin, turning white or gray as it loses
D. Life Expectancy versus Longevity its pigmentation
II. Theories of Aging ● Skin loses its suppleness and accumulates blemishes
A. Error Theory - Wear and Tear ● Individuals appear to shrink as muscle and bone mass are lost
B. Free Radicals and Mitochondrial Theory ● Attention span and recall decline
C. Aging as a Programmed Process ● Death occurs as organs and bodily functions stop to operate
III. Repair Mechanisms to Combat Wear and Tear
A. Enzymatic & Chemical Mechanisms Associated with ROS D. LIFE EXPECTANCY VERSUS LONGEVITY
B. The Integrity of DNA
C. Protein Turnover Life Expectancy  
IV. First-Aging Gene ● Average life span of all births
V. Understanding Underlying Cause of Aging ● Influenced by​ Infant Mortality
VI. Review Questions → If the infant mortality is high, the life expectancy ​decreases
VII. References as compared to longevity
● Average Life Expectancy among Filipinos
OBJECTIVES → Male – 68.99 years
1. Define ageing and describe the effects of ageing → Female – 75.03 years
2. Discuss the different theories of ageing → Infant Mortality – 18.75 deaths/ 1000 live births
→ Error Theory – Wear and Tear
→ Free Radicals and Mitochondrial Theory Longevity  
→ Metabolic Theory ● Expected lifespan only for those persons who survived infancy
→ Aging as a Programmed Process ● For people 5​ years and above
3. Explain repair mechanisms to combat ageing
4. Describe the first ageing gene II. THEORIES OF AGING  
● Aging and death are ​multifactorial processes
I. INTRODUCTION  ● Two schools of thought on Aging and mortality (Harper; Dr.
Balcueva)
A. DEFINITION OF AGEING   → Wear and Tear Theory of Aging
● A biologically determined phenomenon (primary ageing) ▪ Non-determinant / Stochastic​ P ​ rocesses
influenced by ​hostile environmental factors​ (diseases, ▪ Lifetime accumulation of damage from disease or injury
trauma, socioeconomic state). ▪ While the human body has a certain capacity to repair and
● It is a​ time-dependent deterioration​ in function of an organism replace at the molecular and cellular levels, this capacity
(2021B) is variable and finite (Harper’s)
▪ Includes:
Table 1.​ WHO Classification of the Elderly − Error theory​ ​– Wear and Tear
Classification Age Bracket − Free Radicals and Mitochondrial Theory
Middle Age 45 - 59 years old → Programmed Theory of Aging
Presenium 60 - 74 years old ▪ Determinant / Pre-Programmed Processes
Senium 75 - 89 years old ▪ Aging and death are genetically programmed processes
analogous to puberty, which have evolved through a
Very Old 90 years old and above
process of natural selection (Harper’s)
*Senium - the final period in the normal life span (2021B)
▪ Dr. Balcueva: “From birth, individuals experience a lot of
changes and development occurs. These major changes
B. CHARACTERISTICS OF AGEING PROCESS FROM A  only stop when we reach adulthood. During adulthood,
MEDICAL POINT OF VIEW   very little ​physiological​ change takes place, except
● Increased mortality during pregnancy”.
● Changes in biochemical composition of tissues ▪ Example: Menstruation occurs from adolescence to ~45
→ Example: wrinkling due to loss of elasticity of the skin years (Dr. Balcueva)
● Progressive deterioration of physiologic functions ▪ Includes:
→ Barring fatal illness or injury, the onset of the final stage of − Metabolic Theory
life, old age, is signaled by a resurgence of physical and − Apoptosis
physiological change (Harper’s) − Telomeres: Molecular Countdown Clock

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 ▪ The amino groups projecting from the heterocyclic
aromatic rings of the nucleotide bases cytosine, adenine,
A. ERROR THEORY – WEAR AND TEAR  and guanine are each susceptible to ​hydrolytic attack​.
● Due to accumulation of damage over time, particularly in ▪ Nucleotide bases reacted with water that are the DNA of
long-lived cell populations with little turnover the cell can cause mutation, that if left unpaired, can
→ Because of our use and abuse of our body (2021B) potentially perturb gene expression or generate
● Due to ​environmental factors​ that are reactive with organic dysfunctional gene
biomolecules such as proteins, DNA, and lipids ▪ The ​amino group​ is replaced by a ​carbonyl​ group
● The most common agents that cause damage but are ironically − cytosine → uracil
essential for life: − adenine → hypoxanthine
→ Water − guanine → xanthine
→ Oxygen (ROS) ▪ ADENINE: ​Cleavage of the deoxyribose of adenine
→ Sunlight removes the sugar from the nucleotide forming an AP site
(apurinic/apyrimidinic site) also known as an abasic site
Water   (no base)
● Relatively ​weak nucleophile − Base is completely eliminated, hence, a presence of
→ Nucleophile: functional groups rich in electrons and capable gap in the sequence, that if left unpaired, can lead to
of donating them (Lehninger) either a substitution or a frame-shift mutation
● However, because of its ​ubiquity and high concentration
(>55M [Harper’s], 70% of the body [2021B]), even this weak
nucleophile will react with susceptible targets inside the cell
● Reactions with water:
→ Hydrolysis of Peptide Bonds
▪ Peptide bonds: strong, covalent bonds (Dr. Balcueva)
▪ Water cleaves the peptide bonds of proteins causing AAs
to separate and to lose the ability to perform their
functions as proteins
→ Hydrolysis of amide bond in side chain of asparagine
and glutamine
▪ Water will hydrolyze and cleave the amino group of
asparagine​ and ​glutamine​ (which are neutral) and
convert it to ​aspartate​ and ​glutamate​, respectively (which
are acidic) Figure 2.​. Reaction with nucleotide bases in DNA. (C) Net mutation of
▪ The amide bonds most frequently targeted by water are cytosine to uracil by water. (D) Formation of
those found on the side chains of ​asparagine and an abasic site in DNA via hydrolytic cleavage
glutamine​, presumably because they are more exposed, of a ribose-base bond.
on average, to solvent than the amide bonds in the
→ Other bonds broken by hydrolytic reactions
protein’s backbone. (Harper’s)
▪ Ester bonds: bind FAs to their cognate glycerolipids
▪ The amino group will be released as ​ammonia​ and will be
▪ Glycosidic bonds: link monosaccharides and other sugars
replaced by a ​carboxylic acid​ group → negatively
▪ Phosphodiester bonds: hold polynucleotides together, and
charged and capable of attracting a molecule (Dr.
link head groups of phospholipids to their corresponding
Balcueva)
diacylglycerols

Oxygen (Reactive Oxygen Species)   

● When oxygen is released as ​free oxygen​, it will become
Reactive Oxygen Species (ROS), capable of causing severe
damage (Dr. Balcueva)
● Some biological processes that require enzyme-catalyzed
oxidation by molecular oxygen
→ Hydroxylation of proline and lysine side chains in collagen
tissues
▪ If there is no hydroxylation, proline and lysine will not
cross-link which will result in less resiliency/elasticity of
the collagen tissues (2021B)
Figure 1. ​Hydrolysis of amide bond in side chain of asparagine and → Detoxification of ​Xenobiotics​ by ​Chromosome P450
glutamine → Degradation of ​purine nucleotide​ to ​uric acid
→ Reoxidation of prosthetic group of flavin-containing enzyme
→ Reaction with nucleotide bases in DNA (Cytosine, ▪ Catalyzes oxidative decarboxylation and redox reactions
Adenine, Guanine (2021A)
▪ Greater potential biological consequence → ATP synthesis in the mitochondria
▪ Major source of ROS and most damaging

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 ▪ Generation of ​chemiosmotic gradient​ by the Electron molecules, permitting iron to act catalytically producing
Transport Chain (ETC) additional hydroxyl radicals
▪ ETC employs specialized carriers such as ubiquinone and ▪ Haber-Weiss Reaction – ​in the presence of ​oxygen –
cytochromes to safely transport individual, unpaired hydroxyl radical is produced when superoxide and
electrons (2021A) hydrogen peroxide disproportionate
▪ Oxygen is present in ​Complex 4​ and reacts with protons
(Hydrogen ion) to form ​water​ (Last reaction in ETC)
▪ When there is abnormality in the reaction, instead of
reacting to protons, oxygen is released in the cytosol,
producing the ROS ​(2021B; Dr. Balcueva)
→ Synthesis and release of Nitric Oxide
▪ Contains unpaired electron
▪ Important because it relaxes and causes dilatation of
blood vessels → decreasing blood pressure Figure 4​. (B) Generation of Hydroxyl radical via the Fenton reaction. (C)
● Reactive Oxygen Species Generation of hydroxyl radical by the Haber- Weiss reaction.
→ Unpaired, hyper-reactive oxygen​ species (Dr. Balcueva)
● Reactions with ROS
→ Can react with any organic compound and chemically alter
→ Cleavage of covalent bonds
structure and function including protein, nucleic acids, and
▪ Strong bonds
lipids, and can form chain reaction
▪ Example: cleaving bonds between amino acids
→ Chain reactions ​multiply the destructiveness of ROS
→ Formation of ​adducts
▪ A product of a reaction between the free radical and some
▪ Addition of 2 or more compounds with nucleotide bases,
biomolecule is a damaged biomolecule and another
polyunsaturated fatty acids and other compounds with
species with highly reactive unpaired electron
multiple double bonds
▪ The ​chain will terminate​ ​when a free radical is able to
▪ Adducts formed with nucleotide bases can be especially
acquire another lone electron​ to form a relatively
dangerous because of their potential, if uncorrected, to
innocuous electron pair without generating a new
cause misreads during replication that introduce mutations
unpaired electron as a by- product (e.g. one free radical
into DNA (2021A)
encounters another free radical
→ Lipid peroxidation
▪ ROS may be eliminated by ​antioxidant enzymes (​pairs
▪ Formation of cross-linked lipid-lipid or lipid-protein adducts
with oxygen from ROS, stabilizing it)
▪ Destabilizes cell membranes ​(including mitochondrial
→ Examples of ROS
membranes)
▪ Hydroxyl Radical - ​most damaging
▪ Causes leakage of mitochondrial contents (more ROS
▪ Superoxide - second most damaging (Dr. Balcueva
released and damages cells)
▪ Hydrogen Peroxide - mild form and least damaging; can
→ In mitochondria, diminished efficiency in converting reducing
be ​converted ​to hydroxyl radical, which will then produce
equivalents to ATP
severe damage
→ Loss of ​membrane integrity​ due to reaction with ROS can
▪ In increasing reactivity: ​H2O2 < O2 < OH•
trigger apoptosis, the programmed death
▪ If this happens in arteries, there will be loss of elasticity,
leading to ​increased resistance​ and formation of plaques
→ myocardial infarction (Dr. Balcueva)
→ Peroxidation of polyunsaturated lipids;
▪ Oxidation of guanine
▪ Reaction of proteins with ROS

Figure 5.​. ​ROS react directly and indirectly with a wide range of biological
molecules.​ ​ Peroxidation of ​unsaturated lipids ​generates reactive
Figure 3.​ Many types of ROS are encountered in living cells. products such as ​malondialdehyde​ and ​4-hydroxynonenal​.

→ Two pathways wherein hydroxyl radical can be generated

from less destructive ROS:
▪ Fenton Reaction​ – in the presence of ​ferric ion​ – ferric is
converted to ferrous and the other products would be
hydroxyl radical and hydroxyl; The ferrous iron can be
reduced back to ferric state by other hydrogen peroxide

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 → These signals induce the opening of permeability transition
pore complex embedded in the mitochondrial outer
membrane through which molecules of small electron carrier
protein ​cytochrome c​ then escape to the cytoplasm
→ Cytochrome c ​serves as core for apoptosome
→ This initiates a cascade of proteolytic activation events
targeting proenzyme forms of ​caspases
→ Terminal caspases 3 and 7​ break down structural proteins
in the cytoplasm and chromatin proteins in the nucleus
→ These events lead to cell death and affected cell elimination
through phagocytosis

Table 2.​ Genes encoded by the Human Mitochondrial Genome

Genes encoded by the Human Mitochondrial Genome
rRNA 12S, 16S, rRNA
tRNA 22 tRNAs (2 for Leu and Ser)
Subunits of NADH-ubiquinone ND 1-6, ND 4L
oxidoreductase (​Complex
Figure 6​. Guanine can be directly oxidized by ROS to produce 1​,>40 total)
8-oxoguanine​ or form an adduct, ​M1dG​, with the ROS product
malondialdehyde Subunits of Cytochrome b
ubiquinolcytochrome
c oxidoreductase
(​Complex 3​, 11 total)
Subunits for cytochrome COX 1, COX 2, COX 3
oxidase (​Complex 4​, 13 total)
Subunits of F1, F0​ ATPase ATPase 6, ATPase 8
(ATP synthase, 12 total)

UV light
● UV radiation
→ Wavelength of light that lie immediately beyond the blue or
short wavelength of the visible spectrum
→ Strongly absorbed​ by organic compounds possessing
aromatic rings or multiple, conjugated double bonds
such as nucleotide bases of DNA and RNA
→ Prolonged exposure to sunlight can lead to accumulation of
multiple DNA lesions that can overwhelm a cell’s intrinsic
repair capacity

1. Rupture of covalent bonds of proteins

Figure 7.​. Common reactions of proteins with ROS, including oxidation of 2. Cross-linking of proteins
amino acid side chains and cleavage of peptide bonds. Oxygen atoms 3. Generation of free-radicals
derived from ROS are marked in red
4. Formation of ​THYMINE DIMER​ (CYCLOBUTANE RING) in the
DNA when 2 consecutive thymine bases are stacked together
B. FREE RADICALS AND MITOCHONDRIAL THEORY → If two main dimer are stacked together and are exposed to
● Mitochondria​: most ​important source​ of ROS UV light, then the cyclobutane ring will not be formed and
→ Several components of the electron transport system are what will happen is that it will not be read during
encoded by the mitochondrial DNA. replication anymore
→ Mitochondrial genome ​lacks​ ​repair mechanism 5. Repair mechanism- uses ​photolyase
▪ Mitochondrial DNA do not have the capacity to repair → if
one of the genes that are encoded in the mitochondria is
mutated, it will be passed on (Dr. Balcueva)
→ Oxidative damage to the components in this pathway could
lead to increased ​leakage​ of hydrogen peroxide, superoxide
etc. into the cytoplasm (​can damage cell contents​)
→ Slowing rate of ATP synthesis​ could readily lead to types
of wholesale decline in physiologic function that occur in
aging (i.e. ​decreased signs of aging​)
● Mitochondria are key participants in apoptosis
→ ROS, viral dsRNA, DNA damage, and heat shock​ serves
as trigger for apoptosis
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 Figure 9. ​Protein glycation can lead to the formation of
protein-protein cross-links. Shown are the sequence of reactions that
generate the ​Amadori​ ​product​ on the surface of the protein (marked in
green), and the subsequent formation of a protein – protein crosslink via
an amino group on the surface of a second protein (in red) (Harper’s)

Aggregated Proteins  
● Amyloid​ may be produced from the aggregation of proteins
→ Toxic protein aggregates that are formed through the
modification of a proteins composition or conformation that
cause it to adhere to other protein molecules
→ Causes neurodegenerative diseases such as ​Parkinson’s,
Alzheimer’s, Huntington’s disease, Mad Cow’s Disease
(spinocerebellar ataxia, spongiform encephalopathies)
→ This is different from ​amadori product​, which involves ​sugar
[aggregation] ​(Dr. Balcueva)

C. AGING AS PROGRAMMED PROCESS

Figure 8​. Formation of ​thymine dimer (cyclobutane ring)​ in the DNA
following excitation by UV light. Metabolic Theory of Aging
● ”brighter candles burn out quicker”
Protein Glycation   ● Lifespan is linked to ​basal metabolic rate
● Leads to formation of damaging crosslinks ● Suggests that continued generation of energy through
● When amino groups are exposed to a reducing sugar, a consumption of oxygen would lead to accumulation of ROS
reversible adduct is slowly generated through formation of → What is being “counted” is not heartbeats or energy, but the
Schiff base ROS that are by-product of respiration (Harper)
● Schiff base formation between aldehyde or ketone and an → Eating and spending a lot of energy would lead to
amino group accumulation of ROS -> increased signs of aging ->
● Glycated proteins undergo a series of rearrangements to form decreased lifespan
amadori products ​, which contain ​conjugated carbon-carbon → The less energy you spend -> less ROS production -> the
double bonds​ that can react with the amino group of another longer you live
neighboring protein ● Cells experiencing ​caloric deficits​ adjust (reprogram) their
● Amadori product - ​the product of rearrangement of glycated metabolic pathways to utilize available resources in a ​more
protein with ​C=C double bond​; crosslinks with other protein efficient manner​ that concomitantly decreases the yield of
molecule (​Advanced Glycation End product = AGE​) collateral ROS
● Clinical application:
→ AGE formations in the eye -> ​cataract formation Apoptosis Theory 
→ in the arteries -> atherosclerosis (decreased elasticity of ● Programmed​ cell death
blood vessels) ● These are the following indicators for apoptosis:
→ Glycation of RBCs → ROS
→ Viral RNA
→ DNA damage
→ Heat shock

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 Figure 10. ​Apoptosis pathway

Important points mentioned in the lecture  Figure 11. ​The telomerases at the ends of eukaryotic chromosomes
progressively shorten with each cycle of replication
● Apoptosis occurs by ​two pathways
● 1st pathway involve the ​binding of death ligands (TNF-α and
FAS) to death receptors ​in the membrane [Link] REPAIR MECHANISMS COMBAT WEAR 
→ ligand-receptor complex will go to the adapter proteins which AND TEAR 
trigger ​Pro-caspase 8 to become Caspase 8
● The other pathway involves BCL2 and BAX A. ENZYMATIC & CHEMICAL MECHANISMS 
→ BCL2 and BAX have antagonistic reactions ASSOCIATED WITH ROS
→ BAX is apoptotic while BCL2 is anti-apoptotic ● Several powerful ​oxidants​ are produced during the course of
→ If ​BAX predominates, ​it stimulates mitochondria to​ increase metabolism, in both blood cells and most other cells of the body.
permeability ● Oxidants include ​superoxide, hydrogen peroxide, peroxyl
→ Permeability would lead to​ leakage of Cytochrome C radicals, and hydroxyl radicals​, which are referred to as
outside into the cytosol reactive oxygen species (ROS).
→ Will trigger ​Procaspase 9 ​to become ​Caspase 9 ​to join with
Caspase 3 Superoxide dismutase and Catalase
→ Caspase 3 and Caspase 9 triggers digestion of protein ● Protects the cell by converting ​superoxide​ and h
​ ydrogen
and DNA peroxide​, respectively, to ​less reactive products
→ Thereby, preventing potential molecular damage before it
Telomeres occurs
● Shortens each time a eukaryotic cell divides → Reaction for ​Superoxide dismutase
● Cap the ends of eukaryotic chromosomes that provide a source
dispensable DNA to accommodate wastage that occurs when
linear chromosomes are replicated (Harper) → Reaction for ​Catalase
→ Wastage is a consequence of the fact that all DNA
polymerases work unidirectionally, 3’ to 5’
● Replicative senescence - ​mitosis ceases
→ As more cells enter this state, the body progressively loses Glutathione
capacity to replace damaged cells ● Converts​ hydrogen peroxide to water
● Telomerase - ​synthesizes thousands of G-T rich nucleotides at ● Acts as a chemical redox ​protectant​ able to convert hydrogen
the ends of linear DNA molecules that restore their telomeres to peroxide to water
full length; expressed in ​stem cells and cancer cells​ but ​not in ● Reduced glutathione (GSH)​ is important in the metabolism of
somatic cells the RBC, in part to counteract the action of potentially toxic
peroxides; the RBC can synthesize GSH and requires NADPH
to return oxidized glutathione (GSSG) to the reduced state.
● Glutathione​ can also react directly with cysteine sulfenic acids
and disulfides on proteins to ​restore​ them to their ​reduced
state​, and form ​adducts​ with toxic xenobiotics
● Oxidized glutathione​ consists of two tripeptides linked by an
S-S bond which is later reduced to maintain the protectant pool

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● The red blood cells of individuals who are deficient in the activity C. PROTEIN TURNOVER
of glucose-6-phosphate dehydrogenase cannot generate ● Turnover ​- wherein the ​global population​ of a given
sufficient NADPH to regenerate glutathione from oxidized biomolecule is ​degraded​ ​and replaced​ by new synthesis on a
glutathione, which in turn impairs their ability to dispose off continuing or constitutive basis to ​remove aberrant lipids,
H2O2 and oxygen radicals. carbohydrates, and proteins
→ Some proteins, particularly the fibrous proteins that
Antioxidants contribute to the structural integrity of ​tendons, ligaments,
● Tissue damage caused by oxygen radicals is often called bones, matrix​ undergo ​little, if any turnover (accumulate
oxidative damage,​ and factors that protect against oxygen damage)
radical damage are known as ​antioxidants​. ● The most prominent mechanisms for repairing damaged
● Vitamins A, C, and E​ - maintaining the body’s ability to proteins:
neutralize ROS and slow aging. → Target the side chain sulfur atoms of cysteine and
● Oxidative Stress​ - reflects an imbalance between the systemic methionine
manifestation of reactive oxygen species and a biological → Target the isoaspartyl groups​ formed when a peptide bond
system's ability to readily detoxify the reactive intermediates or shifts from an alpha to a side chain carboxyl group
to repair the resulting damage
Targeting the side chain sulfur atoms
B. THE INTEGRITY OF DNA ● Targeting the side chain sulfur atoms (sulfhydryl group) of
● Living organisms possess a ​limited capacity to replace or cysteine and methionine:
repair damaged macromolecules → Glutathione​ reacts directly with cysteine-disulfides, cysteine
→ The majority of this capacity is directed toward maintaining sulfenic acids and methionine sulfoxide to ​regenerate
the integrity of the nuclear (but not the mitochondrial) cysteine and methionine​, respectively.
genome due to: → Disulfide reductase and methionine sulfoxide reductase
▪ DNA’s unique information storage function enzymes ​provide an enzyme-catalyzed reduction
▪ Vulnerability of heterocyclic aromatic nucleotide bases to mechanism using NADPH as electron donor
chemical assault and UV radiation → Unfortunately, the ​reduction potential of glutathione and
▪ Each human cell contains only 1 or 2 copies of each NADPH is only sufficient to reduce the lowest oxidation
chromosome states of the said sulfur atoms: cysteine disulfides, or sulfenic
● Maintaining the integrity of the genome begins at ​replication​, acids and methionine sulfoxide.
where careful proofreading is performed ▪ Cysteine sulfinic acid, cysteine sulfonic acid, and
→ Proofreading ​- ensures that the new genome formed during methioninesulfone are refractory to reduction under
somatic cells division preserves the template directed to its physiologic conditions.
synthesis
→ Note: A ​somatic cell ​is one that forms part of the body of an Targeting the isoaspartyl groups for repair
organism. ● Aspartic acid residues ​possess the precise geometry needed
● Most living organisms possess a ​multilayered system of to enable the side-chain carboxyl group to react with the amino
enzymes,​ whose role is to inspect and correct aberrations that: group within the peptide bond formed with its alpha carboxyl
→ Escaped proofreading group
→ Were generated through the action of water,(double strand → The resulting ​cyclic diamide bond​ can then reopen to form
breaks, loss of a nucleotide base, and deamidation of either the original peptide bond or an isoaspartyl residue in
cytosine) UV radiation (thymine dimers and strand breaks), which the side-chain carboxyl now forms part of the protein’s
or exposure to chemical modifiers (adduct formation) peptide backbone.
● Multilayered system of enzymes is composed of: → Methylation​ of the ​alpha carboxyl group​ provides a leaving
→ Mismatch repair enzymes group that promotes the reformation of the cyclic diamide,
→ Nucleotide excision repair enzymes which can then reopen to form the normal peptide bond
→ Base excision repair enzymes linkage.
→ Ku System ​- used for repairing double-strand breaks in the
phosphodiester backbone of DNA Aggregated Proteins 
● As a last resort, cells harboring damaging mutations are subject ● Aggregated proteins ​are ​highly refractory​ to degradation or
to removal by ​apoptosis repair.
● Despite the precautions used to ensure the fidelity during → modification to a protein’s composition or conformation that
replication and to repair subsequent damage, some mutations cause it to adhere to other protein molecules can lead to the
inevitably slip through formation of toxic aggregates, called ​amyloid​.
→ Somatic Mutation Theory of Aging ● Amyloid
▪ Also serves a driver of the aging process → The toxic effects of these insoluble aggregates are
▪ The ​accumulation of mutant​ cells over time must exacerbated by their presence, as in this state most are
inevitably lead to compromised biological function that generally refractory to the catalytic action of the proteases
manifests itself, at least in part, as the physical changes normally responsible for their turnover
we associate with aging

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Table 3. ​Time required for all of the average cell types to be replaced REVIEW QUESTIONS
Tissue or cell type Turnover
Intestinal epithelium 34 hours 1. Which of the following nucleotide reaction pair caused
Epidermis 39 days by ROS is correct?
Leukocyte < 1 year a. cytosine: xanthine
Adipocyte 9.8 years b. adenine:xanthine
Intercostal skeletal muscle 15.2 years c. guanine: uracil
Cardiomyocyte ≥ 100 years d. adenine: hypoxanthine
2. Arrange ROS in increasing reactivity
IV​. ​FIRST-AGEING​ ​GENE  a. O​2​-​ < OH• < H​2​O​2
● A study by Kenyon and his colleagues observed that worms b. H​2​O​2​ < O​2​-​ < OH•
(​Caenorhabditis elegans)​ carrying mutations of the gene that c. OH• < H​2​O​2​ < O​2​-
encodes an insulin receptor-like molecules, ​DAF-2​, lived 70% 3. Which enzyme/system is used to repair double-strand
longer breaks in the phosphodiester backbone of DNA?
● For a gene to be quantified as an “aging gene” (2021B): a. Mismatch repair enzymes
→ Manipulation does not just prolong old age by delaying the b. Nucleotide excision repair enzymes
point at which life ceases c. Yu System
→ It must impact the schedule of changes associated with d. Ku System
aging. 4. These are cross-linked aggregates formed through
● Code for transcription factors ​PHA-4 or DAF-16 covalent crosslink between two proteins which undergo
→ Presumably controls the expression of aging critical genes further glycation
→ Prolongs old age a. Amadori product
→ Delays changes associated with old age b. AGE
● DAF-​2 -> activate PHA-4, DAFs -> control gene expression of c. ROS
aging genes d. Schiff base

V​. ​UNDERSTANDING UNDERLYING CAUSE OF AGEING 

● Causes of aging: Answers: d, b, d, b
→ Genomic instability
→ Telomere attrition REFERENCES 
→ Epigenetic alterations [BCH]2019/04/08. ​Biochemistry of Aging. ​Dr. Lourdes L. Balcueva.
→ Loss of proteostasis (protein homeostasis) Dr. Balcueva’s Powerpoint and Lecture Recording
▪ Presence of nonnative protein aggregates in tissues Harper’s Illustrated Biochemistry 30th edition, chapter 58
→ Deregulated nutrient sensing 2021A and 2021B Trans
▪ Need for caloric monitoring → less ROS Lehninger Principles of Biochemistry (7th ed.).
→ Mitochondrial dysfunction
→ Cellular senescence
→ Stem cell exhaustion
→ Altered intercellular communication
● By slowing down or stopping some degenerative processes that
can render the last stage of life more meaningful, productive,
and significant.

Figure 12​. Hallmarks of Aging

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