Theory of Aging (Biology and genetic of Aging) · Aging and some aging-related diseases are linked...
Transcript of 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
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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6. Mitochondrial Dysfunction
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
6. Mitochondrial Dysfunction
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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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The Top 10 Hot Topics in Aging
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 Top 10 Hot Topics in Aging
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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The Top 10 Hot Topics in Aging
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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The Top 10 Hot Topics in Aging
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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