Molecular and Genetic Aspects of Aging

MOLECULAR AND GENETIC
ASPECTS OF AGING
Introduction:
The role of genetics in determining life-span is complex and paradoxical.
Although the heritability of life-span is relatively minor, some genetic variants
significantly modify senescence of mammals and invertebrates, with both
positive and negative impacts on age-related disorders and life-spans. In certain
examples, the gene variants alter metabolic pathways, which could thereby
mediate interactions with nutritional and other environmental factors that
influence life-span. Given the relatively minor effect and variable penetrance of
genetic risk factors that appear to affect survival and health at advanced ages,
life-style and other environmental influences may profoundly modify outcomes
of aging.
GENETICS
OCCURRENCE DECLINE OF
OF MOLECULAR METASTATIC ORGAN-
HALLMARKS OF SYSTEM LEVEL
AGING PGYSIOLOGICA
AGING
L FUNCTION
BIOLOGICAL
AGING
Literature Survey:
The genetics analysis of life span has only begun in mammals, invertebrates,
such as Caenorhabditis elegans and Drosophila, and yeast. Even at this
primitive stage of the genetic analysis of aging, the physiological observations
that rate of metabolism is intimately tied to life span is supported. In many
examples from mice to worms to flies to yeast, genetic variants that affect life
span also modify metabolism. Insulin signaling regulates life span coordinately
with reproduction, metabolism, and free radical protective gene regulation in C.
elegans. This may be related to the findings that caloric restriction also
regulates mammalian aging, perhaps via the modulation of insulin-like signaling
pathways. The nervous system has been implicated as a key tissue where
insulin-like signaling and free radical protective pathways regulate life span
in C. elegansand Drosophila. Genes that determine the life span could act in
neuroendocrine cells in diverse animals. The involvement of insulin-like
hormones suggests that the plasticity in life spans evident in animal phylogeny
may be due to variation in the timing of release of hormones that control vitality
and mortality as well as variation in the response to those hormones. Pedigree
analysis of human aging may reveal variations in the orthologs of the insulin
pathway genes and coupled pathways that regulate invertebrate aging. Thus,
genetic approaches may identify a set of circuits that was established in
ancestral metazoans to regulate their longevity.
Cell Aging :DNA damage And Telomeres :
A principal factor in aging is an exponential increase in incidence and mortality

rates of cancer and non-cancerous diseases, as well progressive tissue
degeneration and atrophy, caused by a decrease in adult or somatic stem cell
function
Cells are constantly exposed to a harmful environment throughout life.

Increasing cell damage contributes to the dysfunction that characterizes the
aging body. The best example of DNA damage as a cause of aging are the
progeroid syndromes, which are caused by a deficiency in the mechanisms
involved in DNA repair and whose symptoms begin early in life
Mutations in certain genes confer greater stress resistance and a reduced rate of
damage accumulation, increasing longevity. For example, mutation in the gene
that encodes the oxidative stress response protein p66shc, which prolongs life and
protects from a variety of aging-associated diseases in mice, enhances resistance
to apoptosis following oxidative stress in vitro-cultured cells [
Telomeres are DNA-protein complexes that cap the ends of linear DNA strands,
stabilizing them and preventing chromosome instability . A correlation has been
proposed between telomere shortening and somatic stem cell decline during
aging. The enzyme telomerase adds specific DNA sequence repeats to the
chromosome ends that are lost through cell division, thus restoring telomere
length and delaying cell senescence, apoptosis, and death . The repetitive DNA
at chromosome ends shortens with age, as observed in fibroblasts, lymphocytes,
and hematopoietic stem cells (HSC) . Telomeres become critically short after
repeated mitotic divisions without adequate telomerase activity, making cells
susceptible to apoptosis, death and to a clear increase in mutation
Telomere shortening is associated with age-related diseases in humans ,and

patients with accelerated aging syndromes show a higher rate of telomere
erosion and marked chromosome instability. Consistent with this, telomere
dynamics are important for HSC maintenance , telomere shortening impairs
adult stem cell function , and telomerase-deficient mice have short telomeres
and age prematurely ; most strikingly, telomerase-overexpressing mice have
longer telomeres and show delayed aging and cancer resistance . The pathways
that involve DNA sequence alterations in somatic stem cell aging are still
unclear, but these findings raise the possibility that telomere length or
deficiencies in DNA repair systems could be part of these routes.
Some researchers shed light on gene mutation-caused progeroid syndromes,

such as Hutchinson-Gilford progeria syndrome (HGPS), Werner syndrome,
Rothmund Thomson syndrome, Cockayne syndrome, ataxia-telangiectasia, and
Downsyndrome*3. Gene mutation is inherited and causes progeria, a type of
premature aging, often showing accelerated skin aging phenotype, including
skin
atrophy and sclerosis, poikiloderma, alopecia, thinning, and graying of the
hair53, for example, HGPS is caused by the mutation of gene LMNA54, which
produces progerin, a mutant protein that impairs many important cellular
processes55. More work is being done to try to gain insight into genetic
variation during the aging process. In 2014 and 2017, different groups identified
single-nucleotide polymorphisms associated with skin aging in Caucasians and
the Chinese Han population,respectively.
SYNDROME GENE FUNCTION
Cockayne Syndrome ERCC6(CSA) DNA repair
ERCC8 (CSB)
Fanconi Anemia FANCA. FANCB. FANCC. DNA repair
FANCD1. FANCD2. FANCE.
FANCE. FANCG
FANCI, FANCJ, FANCL,
FANCM
FANCN
Werner Syndrome WRN DNA helicase
(WS)
Bloom Syndrome RECQLA DNA helicase
Hutchinson-Gilford LMNA Structural
Syndrome Protein
Aging is characterized by a progressive decline in physical, mental, and
reproductive capacity, as well as an increase in morbidity and mortality.
Damage invariably accumulates with age and contributes to the cell
dysfunction that characterizes this process, and is clearly influenced by
genetic and environmental factors. The effects of the variety of factors
involved in aging are the result of the balance between our defense and
damage repair systems and the aggression to which we are subjected .
Defense and repair systems are highly enzyme dependent; the absence or
malfunction of a gene necessary for production and activity of these
enzymes can lead to accumulation of cell damage, as demonstrated by
the progeria syndromes.
There is increasing evidence that, in addition to genetic factors, age-

associated alteration of gene function might also depend on epigenetic
factors. Examples of epigenetic alterations with age include global DNA
hypomethylation and promoter hypermetylation. Thus, aging is not
probably mediated by a single gene or main mechanism. The magnitude of
the contribution of the pathways cited above to the onset and progression
of aging and age-related diseases remains unclear. Many questions
regarding epigenetic and its role in age related diseases still remain open,
but may be able to explain many of the phenotypic changes related to the
aging process. Further studies are needed to describe the pathways
involved in age-related physiological alteration (hypertension, insulin
resistance) and predisposition to age-related pathological changes (cancer,
neurodegenerative disease). Exploration of these functional connections
might provide options to help develop more efficient anti-aging strategies
to ameliorate senescence-related diseases. Exploration of these functional
connections might provide options to help develop more efficient anti-
aging strategies to ameliorate senescence-related diseases.
[1] Fraga MF, Esteller M. Epigenetics and aging: the targets and the marks. Trends
Genet. 2007;23:413–418. [PubMed]
[2] Fraga MF, Agrelo R, Esteller M. Cross-talk between aging and cancer: the
epigenetic language. Ann N Y Acad Sci. 2007;1100:60–74. [PubMed]
[3] Flores I, Cayuela ML, Blasco MA. Effects of telomerase and telomere length on
epidermal stem cell behavior. Science. 2005;309:1253–1256. [PubMed]
[4] Sharpless NE, DePinho RA. How stem cells age and why this makes us grow
old. Nat Rev Mol Cell Biol. 2007;8:703–713.[PubMed]

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MOLECULAR AND GENETIC

Cell Aging :DNA damage And Telomeres :

A principal factor in aging is an exponential increase in incidence and mortality

Cells are constantly exposed to a harmful environment throughout life.

Telomere shortening is associated with age-related diseases in humans ,and

Some researchers shed light on gene mutation-caused progeroid syndromes,

There is increasing evidence that, in addition to genetic factors, age-

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