2. What is Ageing
Aging is the result of the progressive and irreversible decline of the
capacity of an organism to adapt to its ever-changing
environment.
Its multiple causes are all progressive, irreversible and harmful
ultimately leading to death
4. Cellular Ageing
Cellular Ageing is the progressive decline in cellular function
and viability caused by genetic abnormalities and the
accumulation of cellular and molecular damage due to the
effects of exposure to exogenous influences
6. Theories of Ageing
ï” The knowledge regarding human ageing process is still obscure in some of its aspects
ï” Many theories have been proposed to explain the process, but they are all specific of a
particular cause of ageing; a global view of them is needed
8. Evolutionary theory
âą Accumulation of DNA mutations after several cell
cycles leads to cessation of further division
Mutation Accumulation
âą Result of natural degrading process that leads to
accumulation of damage which can be repaired at the
expense of reproduction
Disposable soma
âą Some traits that increase fitness early in life may also
have negative effects later in life.
Antagonistic pleiotropy
9. Molecular Theory
ï” GENE REGULATION: Ageing is caused by changes in expression of genes regulation
ï” CODON RESTRICTION: Accuracy of mRNA translation is impaired due to inability to
decode codon in mRNA.
ï” ERROR CATASTROPHE: Decline in correct gene expression results in increased
fraction of abnormal proteins..
ï” SOMATIC MUTATION: Molecular damage accumulates due to DNA damage.
ï” DYSDIFFERENTIATION: Gradual accumulation of molecular damage impairs gene
expression. regulation.
10. Cellular Theory
ï” TELOMERE THEORY : Senescence results from telomere loss with each cell cycle.
ï” FREE RADICAL THEORY : Oxidative mechanisms produce highly reactive free
radicals that subsequently damage proteins, lipids, & DNA.
ï” WEAR & TEAR THEORY : Accumulation of normal injury leads to senescence.
ï” APOPTOSIS : Programmed cell death from genetic events or genome crisis
11. Systemic Theory
âą Alterations in neuroendocrine control of
homeostasis results in ageingNEUROENDOCRINE
âą Assumes a fixed amount of metabolic period
for every living organism. (LIVE FAST, DIE
YOUNG)
RATE OF LIVING
12. Theories of Ageing
ï” The search for a single cause of ageing has recently been replaced by the view of ageing
as an extremely complex, multifactorial process.
ï” Therefore, the different theories of aging are not mutually exclusive, but complementary
of others in the explanation of the normal aging process
18. DNA Repair and Senescence
Monitors integrity of
DNA before replication.
Pauses cell cycle
for DNA repair
G1/S
Monitors integrity of
DNA after replication so
that it can enter mitosis
DNA damaged beyond repair
Non-replicative state
(SENESCENCE)
G2/M
19. Telomeres
Cellular Senescence: Normal cells have a limited capacity for replication. After a fixed no. of
divisions cells become arrested in a terminally non dividing state, known as replicative
senescence
ï” Chromosomes end with repeats of conserved âTTAGGGâ sequence - interact with specific
proteins -looped conformation- protects chromosomal DNA from degradation
23. Defective Protein homeostasis
ï” Maintenance of protein quality, or proteostasis, is critical for the health and
longevity of the cell
ï” Proteostasis ensures a supply of high-quality protein by culling misfolded and
damaged proteins from the cellular pool and replacing them with newly formed
proteins
ï” Disruption of proteostasis is hastened by stress and signals organismal ageing
24. ï” Chaperones, include small heat
shock proteins, as well as SOD
and catalase
ï” direct AA chains to the correctly
folded state, misfolded proteins
to degradation pathways &
refold misfolded proteins
ï” UPR monitors quality of
unfolded AA chains primarily in
the ER: ER-associated
degradation (ERAD) pathway
.
Molecular chaperones
25. Autophagy-Lysosome
System
âș Autophagy is required for
longevity
âș Inhibition of autophagy
generates hallmarks of aging at
an accelerated rate
âș Autophagic clearing of
damaged proteins, protein
aggregates, organelles, lipids,
etc is required to provide new
raw material for a healthy cell.
26. Nutrient Sensing
ï” Dietary restriction (DR), a reduction in food intake without malnutrition, extends the
average and/or maximum life span of various organisms
ï” Causes a reduction in metabolic markers of several diseases, including diabetes,
cardiovascular disease and cancer increasing longevity
27. Insulin and insulin-like growth factor(IIS)
Caloric restriction
- âinsulin and insulin-like growth factorâ(IIS)
leads to increased life span and resistance to age-related pathologies
- Ribosomal S6 protein kinase 1 (S6K1)
RAS
FOXO, a transcription factor
- mammalian Target of Rapamycin
serine/threonine-protein kinase
AKT
28. Sirtuins
ï” Sirtuins are a family of proteins that act as NAD(+) dependent histone deacetylases, which help
control gene expression coding for various proteins
ï” Sirtuins detect when energy levels are low by sensing the coinciding increase of NAD+.
They also
help control catabolic metabolism
stimulate protein folding
inhibit harmful effects of ROS.
ï” Upregulating sirtuins produces anti-aging or health-promoting effects
30. Disorders of Premature Ageing
HUTCHINSON GUILFORD PROGERIA
ï” Male pattern baldness
ï” Cataracts
ï” Life span :10 yrs.
ï” Mutation in LMNA gene (codes for protein Laminin A)
ï” Defective precursor (PROGERIN)
ï” Interferes with organisation of nuclear heterochromatin
which regulates expression of various genes
31. Disorders of Premature Ageing
ATAXIA TELENGIECTASIA
ï” Manifestation of ageing at increased rate.
ï” Mutation in gene encoding for protein involved in repairing double
stranded breaks in DNA.
32. Premature Ageing Disorders
DOWNâS SYNDROME
ï” Patients generally age more rapidly.
ï” Their fibroblasts are capable of fewer cell divisions in culture than those
from age matched controls.
ï” The loss of telomeres was shown to be more rapid in lymphocytes
isolated from the blood of trisomic patients in accord with their more
rapid aging.
33. A list of syndromes carrying defect in genome maintenance
34. A list of syndromes carrying defect in Genome Maintenance
38. SENESCENCE âPOSITIVE ASPECT
Senescence functions as a tumour suppressing
mechanism limiting cell proliferative capacity in vivo
implying that replicative senescence did not evolve to
cause ageing but is rather a consequence of a biological
device that suppresses tumour formation.
Aging can be considered at diff level. It can beâŠAging of organism as a whole is studied
Aging of different cells
Gave The Theory of Programmed Death. He was one of the first scientist to use evolutionary arguments to explain aging. Harman proposed the Free Radical Theory of Aging in 1956 and in 1972 extended the idea, developing the "mitochondrial theory of aging" The cellular senescence theory of aging was formulated in 1965 by hayflick& moorhead. cell senescence was described as the process occurring in normal human cells in culture and characterized by a limited number of cell div
.despite the recent dev in science, the knowâŠâŠMany theories have been proposed of which the major ones can be devided into
The major and most accepted theories can be divided into
Evolutionary theory indicates aging as the result from a decline in the force of natural selection. âŠ.. It was refuted until recently and is now agin being considered and studiedâŠ.disposable soma theory of agingâ argues that the somatic organism is effectively maintained only for reproductive success; afterwards it is disposable.
Free radical.it is among the most accepted theories of aging. It states that
Are subjected to indiscriminate dam such as âŠ. Any acquired error leads to permanent damage which has anâŠ
diet, lifestyle, drugs (e.g. tobacco and alcohol) and radiation etc. cause free radical production within the body.
However, there is also natural production of free-radicals within the body. This is the result of the production of ATP, particularly from the mitochondria, oxygen is a potent free-radical producer.
Free radicals attack the structure of cell membranes, which then create metabolic waste products. Such toxic accumulations interfere with cell communication, disturb DNA, RNA and protein synthesis,
Free radicals can however be transformed by free-radical scavengers
various agents cause different types of dna damage
cellular function relies heavily on the integrity of the genome, which must be preserved. This is why there are several DNA damage repair and checkpoint systems that enables cell survival or triggers senescence or cell death when DNA is damaged
Our chromosomes end with repeats of conserved âTTAGGGâ sequence known as telomeres. These sequences interact with specific proteins & attain a looped conformation- protects chromosomal DNA from degradation and fusion
When somatic cells replicate, a small section of the telomere is not duplicated and telomeres become progressively shortened. As the telomeres become shortend, the ends of ch. Are not protected and r seen as broken dna. Signalling cell cycle arrest
Telomere length can be prevented from shortening by an enzyme Telomerase. Telomerase is a specialized RNA-protein complex that uses its own RNA as a template for adding nucleotides to the ends of chromosomes
 (a)Telomerase enzyme -active in germline and stem cells -and maintains their telomere length by adding âTTAGGGâ repeats to the ends of chromosomes. Therefore, telomeres do not shorten in these types of cells. (b) Telomerase- inactive in normal somatic cells- lose telomeres over time - length reaches below a critical limit- senesce or die(c) In the abs of appropriate signals, continued cell division leads to severe telomere shortening and genomic instability. Cells which survive this crisis, activate a telomere maintenance mechanism& become oncogenic & have very short but stable telomeres
Unfolded protein response
The second mechanism of protein homeostasis is the
It has been seen that DR Including caloric restriction (CR), restriction of major dietary components or intermittent fasting. Other than the indirect pathways, it also causesâŠ
Major features of cellular aging. As the cell ages, translational defects & entropy progressively inc the amt of cell damage& clearance and quality ctrl mech grow less effective.
(a) In a young cell, most organelles are healthy& when proteins acquire damage, they are cleared either by ERAssoDegradation (in the ER) or autophagy (in the cytosol). (b) In an older cell, accumulated damage leads to a less healthy cell. ROS build up from damaged mitochondria and contribute to a greater fraction of the proteome consisting of damaged proteins and protein aggregates
Causing both accelerated ageing and cancer predisposition
Table 5shows a list of age related diseases with the indication of their approximate age of onset. Articular pathology, osteoarthritis starts the earliest. This original matrix is progressively destroyed and replaced by a fibrous matrix. Ensuing inflammation will continue to destroy the original cartilage matrix