theory of aging (biology and genetic of aging) · aging and some aging-related diseases are linked...

Theory of Aging

(Biology and genetic of Aging)

SCBM 304

BIOLOGICAL SCIENCES OF AGING

Lect. Dr. Witchuda Payuhakrit

[email protected]

Objectives

Understand the biology of aging

Describe the hallmarks of aging

Understand the molecular basis of aging

Understand the current research in aging

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Aging

Progressive loss of

physiological integrity

Impaired function and

increased vulnerability to

death

Primary risk factor for

major human

pathologies

After reproductive age

Woman = after menopause

Man = after loss of fertility

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Why should we study aging?

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Why should we study aging?

Diseases associated with aging will pose a huge social and

economic burden

To achieve health lifespan extension in humans, we must

understand which cellular programs are responsible for aging 5

Longest-lived Human

Jeanne Louise Calment

21 February 1875 to 4 August

1997

122 years and 164 days

Longest confirmed human life

span in history

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Factors contributing to lifespan

Genes

Environment Behavioral

traits

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Lessons from Centenarians: Okinawas

Genetic and environment

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Lessons from Centenarians: Ashkenazi Jews

Large genetic component

Likely to be passed from generation to generation

Correlated with high HDL and low LDL

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Behavioral traits: Calorie Restriction

Reduction in calories without malnutrition

May mimic natural periods of nutrient scarcity

In the experiment, calories are reduced 10-30%

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Calorie restriction extends lifespan in rodents

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Calorie Restriction in Primates

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Could Calorie Restriction Work in Humans?

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Biological aging is a decline in function over time, beginning after the

reproductive years

Diseases of aging can affect many systems of human body

Aging can be controlled by complex genetics and by diet

Biology of aging

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The Hallmarks of Aging

Nine candidate hallmarks that are generally considered to

contribute to the aging

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1. Genomic Instability

The accumulation of genetic damage throughout life

Challenged by exogenous and endogenous threats

The genetic lesions include point mutations, translocations,

chromosomal gains and losses, telomere shortening, and

gene disruption

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1.Genomic Instability

Genomic instability and telomere attrition. BER, base excision repair; HR,

homologous recombination; NER, nucleotide excision repair; NHEJ,

nonhomologous end-joining; MMR, mismatch repair; ROS, reactive oxygen

species; TLS, translesion synthesis; SAC, spindle assembly checkpoint 18

2. Telomere Attrition

Most mammalian somatic cells do not express telomerase

Experimental stimulation of telomerase can delay aging in mice

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3. Epigenetic Alterations

A variety of epigenetic alterations affects all cells and

tissues throughout life

DNA Methylation Loci, including those corresponding to

various tumor suppressor genes and Polycomb target genes,

actually become hypermethylated with age

Histone Modifications Inhibition of histone demethylases (for

H3K27) in worms may extend lifespan. In mammals, at least

three members of the sirtuin family—SIRT1, SIRT3 and SIRT6—

contribute to healthy aging

Chromatin Remodeling The associated enzymes levels are

diminished in both normally and pathologically aged cells

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3. Epigenetic Alterations

Epigenetic alterations. Alterations in the methylation of DNA or acetylation and

methylation of histones, as well as of other chromatin-associated proteins, can

induce epigenetic changes that contribute to the aging process.

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4. Loss of Proteostasis

Aging and some aging-related diseases are linked to

impaired protein homeostasis or proteostasis

Mechanisms of folded proteins (the heat- shock family of

proteins) and the degradation of proteins (proteasome or

the lysosome)

Chronic expression of unfolded, misfolded, or aggregated

proteins contributes to the development of some age-

related pathologies, such as Alzheimer’s disease,

Parkinson’s disease, etc.

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4. Loss of Proteostasis

Endogenous and exogenous stress causes the unfolding of proteins (or impairs

proper folding during protein synthesis) 23

5. Deregulated Nutrient Sensing

Insulin and IGF-1 signaling pathway is the most conserved

aging-controlling pathway

Its multiple targets are the FOXO family of transcription

factors and the mTOR complexes, which are also involved

in aging and conserved through evolution

Genetic polymorphisms or mutations that reduce the

functions of these genes have been linked to longevity,

both in humans and in model organisms

Dietary restriction (DR) increases lifespan or health span in

all investigated eukaryote species, including nonhuman

primates

Anabolic signaling accelerates aging and decreased

nutrient signaling extends longevity

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5. Deregulated Nutrient Sensing

Deregulated nutrient sensing. Overview of the somatroph axis involving growth

hormone (GH) and the insulin/insulin growth factor 1 (IGF-1) signaling pathway and

its relationship to dietary restriction and aging 25

6. Mitochondrial Dysfunction

As cells and organisms age, the efficacy of the respiratory

chain tends to diminish, thus increasing electron leakage

and reducing ATP generation

The mitochondrial free radical theory of aging proposes

that the progressive mitochondrial dysfunction that occurs

with aging results in increased production of ROS

Mitohormesis Mild respiratory deficiencies may increase

lifespan whereas severe mitochondrial dysfunction is

pathogenic

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Mitochondrial dysfunction. Mitochondrial function becomes perturbed by aging-

associated mtDNA mutations, reduced mitochondriogenesis, destabilization of the

electron transport chain (ETC) complexes, altered mitochondrial dynamics, or

defective quality control by mitophagy 27


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7. Cellular Senescence

Cellular senescence can be defined as a stable arrest of

the cell cycle coupled to stereotyped phenotypic changes

Some studies have directly used senescence-associated β-

galactosidase (SABG) to identify senescence in tissues

Because the number of senescent cells increases with

aging, it has been widely assumed that senescence

contributes to aging

Senescence β-Galactosidase Staining

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7. Cellular Senescence

Cellular senescence. In young organisms, cellular senescence prevents the

proliferation of damaged cells, thus protecting from cancer and contributing

to tissue homeostasis 30

8. Stem Cell Exhaustion

The decline in the regenerative potential of tissues is one of

the most obvious characteristics of aging

Studies on aged mice have revealed an overall decrease in

cell-cycle activity of hematopoietic stem cells (HSCs), with

old HSCs undergoing fewer cell divisions than young HSCs

Recent promising studies suggest that stem cell rejuvenation

may reverse the aging phenotype at the organismal level

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8. Stem Cell Exhaustion

Stem cell exhaustion. Consequences of the exhaustion of hematopoietic stem

cells (HSCs), mesenchymal stem cells (MSCs), satellite cells, and intestinal

epithelial stem cells (IESCs) are exemplified

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9. Altered Intercellular Communication

Aging also involves changes at the level of intercellular communication,

be it endocrine, neuroendocrine, or neuronal

A prominent aging-associated alteration in intercellular communication

is ‘‘inflammaging,’’ i.e., low-grade chronic systemic inflammation

established during physiological aging

A novel link between inflammation and aging derives from the recent

finding that inflammatory and stress responses activate NF-kB in the

hypothalamus and induce a signaling pathway that results in reduced

production of gonadotropin-releasing hormone (GnRH) by neurons

Contagious aging or bystander effects in which senescent cells induce

senescence in neighboring cells via gap-junction-mediated cell-cell

contacts and processes involving ROS

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9. Altered Intercellular Communication

Altered intercellular communication. Examples of altered intercellular

communication associated with aging

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Functional Interconnections between the Hallmarks of Aging

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Interventions that Might Extend Human Health span

The nine hallmarks of aging are shown together with those therapeutic

strategies for which there is proof of principle in mice

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The Top 10 Hot Topics in Aging

A decline in physical performance

Central nervous system damage Alzheimer’s disease

1. Cognitive decline

2. Depression

Highlighting the need for continued screening

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Habitual walking has been shown to decrease the onset of

physical disability in older persons

3. Mobility

4. Nutrition

Physiological anorexia of aging

The management of weight loss in older persons have

included using taste enhancers

The role of dietary restriction as a means to extend life span

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The hormonal replacement will reverse the stigmata of aging

Estrogen/Progesterone replacement

Testosterone replacement

5. The hormonal fountain of youth

6. Frailty/Sarcopenia

Sarcopenia is a major proximate occurrence in the

development of frailty

Frailty appears to be an important precursor of disability

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Cardiovascular disease is present in over half of the older

population

The management of hypertension in older persons

7. Cardiovascular disease

8. Immune systems and aging

The deterioration of the immune system with aging is well

recognized

Older persons have worse outcomes when exposed to

some of the infectious disease

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Genetic keys of longevity

The mechanism of cellular senescence

Telomerase

Modern embryonic stem cell research for future tissue

rejuvenation

9. The merchants of immortality

10. Systems in geriatrics

Improve care of elderly patients

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Conclusion of research in aging

Understand the mechanism and screening of early

declining process

Study the new strategies to delay the aging processes

and extends the lifespan

Improve care of elderly patients

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Blasco MA. Telomere length, stem cells and aging. Nat Chem

Biol. 2007;3(10):640-9

Cha JY, Kim J, Kim TS, Zeng Q, Wang L, Lee SY, et al. GIGANTEA is

a co-chaperone which facilitates maturation of ZEITLUPE in the

Arabidopsis circadian clock. Nat Commun. 2017;8(1):3

Cholewa JM, Dardevet D, Lima-Soares F, de Araujo Pessoa K,

Oliveira PH, Dos Santos Pinho JR, et al. Dietary proteins and

amino acids in the control of the muscle mass during

immobilization and aging: role of the MPS response. Amino

Acids. 2017

John E. Morley. The Top 10 Hot Topics in Aging. Journal of

Gerontology. 2004; 59:24-33

References

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DiLoreto R, Murphy CT. The cell biology of aging. Mol Biol Cell.

2015;26(25):4524-31

Finkel T, Serrano M, Blasco MA. The common biology of cancer

and ageing. Nature. 2007;448(7155):767-74

Kaeberlein M. Molecular basis of ageing. EMBO Rep.

2007;8(10):907-11

Lopez-Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G. The

hallmarks of aging. Cell. 2013;153(6):1194-217

Mattison JA, Colman RJ, Beasley TM, Allison DB, Kemnitz JW, Roth

GS, et al. Caloric restriction improves health and survival of

rhesus monkeys. Nat Commun. 2017;8:14063

References

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Ogawa T, Irikawa N, Yanagisawa D, Shiino A, Tooyama I, Shimizu

T. Taste detection and recognition thresholds in Japanese

patients with Alzheimer-type dementia. Auris Nasus Larynx.

2017;44(2):168-73

Xie HF, Liu YZ, Du R, Wang B, Chen MT, Zhang YY, et al. miR-377

induces senescence in human skin fibroblasts by targeting DNA

methyltransferase 1. Cell Death Dis. 2017;8(3):e2663

Finkel T, Serrano M, Blasco MA. The common biology of cancer

and ageing. Nature. 2007;448(7155):767-74

S. Park, et al. Neuropeptide Y resists excess loss of fat by lipolysis

in calorie-restricted mice- a trait potential for the life-extending

effect of calorie restriction. Aging Cell. 2017;16: 339-348

References

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