cellular ageing- theories, causes and effects- general pathology based on robbins textbook

1. Cellular Ageing
-MUNIRA SAEED

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

3. Ageing At Different Levels
Organismal level
Cellular level

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

5. History
August Weismann
(1882)
Denham Harman
(1956)
Hayflick &
Moorhead (1962)

6. Theories of Ageing
 The knowledge regarding human ageing process is still obscure in some of its aspects
 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

7. Theories of Ageing
EVOLUTIONARY
MOLECULAR
CELLULAR
SYSTEMIC

8. Evolutionary theory
• Accumulation of DNA mutations after several cell
cycles leads to cessation of further division
Mutation Accumulation
• Result of natural degrading process that leads to
accumulation of damage which can be repaired at the
expense of reproduction
Disposable soma
• Some traits that increase fitness early in life may also
have negative effects later in life.
Antagonistic pleiotropy

9. Molecular Theory
 GENE REGULATION: Ageing is caused by changes in expression of genes regulation
 CODON RESTRICTION: Accuracy of mRNA translation is impaired due to inability to
decode codon in mRNA.
 ERROR CATASTROPHE: Decline in correct gene expression results in increased
fraction of abnormal proteins..
 SOMATIC MUTATION: Molecular damage accumulates due to DNA damage.
 DYSDIFFERENTIATION: Gradual accumulation of molecular damage impairs gene
expression. regulation.

10. Cellular Theory
 TELOMERE THEORY : Senescence results from telomere loss with each cell cycle.
 FREE RADICAL THEORY : Oxidative mechanisms produce highly reactive free
radicals that subsequently damage proteins, lipids, & DNA.
 WEAR & TEAR THEORY : Accumulation of normal injury leads to senescence.
 APOPTOSIS : Programmed cell death from genetic events or genome crisis

11. Systemic Theory
• Alterations in neuroendocrine control of
homeostasis results in ageingNEUROENDOCRINE
• Assumes a fixed amount of metabolic period
for every living organism. (LIVE FAST, DIE
YOUNG)
RATE OF LIVING

12. Theories of Ageing
 The search for a single cause of ageing has recently been replaced by the view of ageing
as an extremely complex, multifactorial process.
 Therefore, the different theories of aging are not mutually exclusive, but complementary
of others in the explanation of the normal aging process

13. Mechanism of Cellular Ageing

14. DNA damage and ageing
All biomolecules (proteins, lipids and
nucleic acids) -indiscriminate
damage - spontaneous reactions
(hydrolysis); numerous endogenous
& exogenous reactive agent -
accounts for ageing
Other macromolecules -
renewable, whereas nDNA -
irreplaceable; any acquired
error – permanent - irreversible
consequences

15. DNA damage: Causes
 Endogenous factors
- Errors in proofreading
- Deamination of bases
- Depurination/Depyrimidination
- Byproducts of normal cellular
processes (ROS)
 Spontaneous(Hydrolysis)
 Exogenous factors
- UV irradiation (sunlight)
- High energy irradiation (x-
rays)
- Mutagenic chemicals
(Mustard gas, cigarette smoke,
food additives)

16. Role of Free radicals

17. Types of DNA damage

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
 Chromosomes end with repeats of conserved ‘TTAGGG’ sequence - interact with specific
proteins -looped conformation- protects chromosomal DNA from degradation

20. Telomere Attrition

21. Telomerase

23. Defective Protein homeostasis
 Maintenance of protein quality, or proteostasis, is critical for the health and
longevity of the cell
 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
 Disruption of proteostasis is hastened by stress and signals organismal ageing

24.  Chaperones, include small heat
shock proteins, as well as SOD
and catalase
 direct AA chains to the correctly
folded state, misfolded proteins
to degradation pathways &
refold misfolded proteins
 UPR monitors quality of
unfolded AA chains primarily in
the ER: ER-associated
degradation (ERAD) pathway
.
Molecular chaperones

25. Autophagy-Lysosome
System
► Autophagy is required for
longevity
► Inhibition of autophagy
generates hallmarks of aging at
an accelerated rate
► Autophagic clearing of
damaged proteins, protein
aggregates, organelles, lipids,
etc is required to provide new
raw material for a healthy cell.

26. Nutrient Sensing
 Dietary restriction (DR), a reduction in food intake without malnutrition, extends the
average and/or maximum life span of various organisms
 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
- “insulin and insulin-like growth factor”(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
 Sirtuins are a family of proteins that act as NAD(+) dependent histone deacetylases, which help
control gene expression coding for various proteins
 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.
 Upregulating sirtuins produces anti-aging or health-promoting effects

29. Cellular Ageing: Overall View

30. Disorders of Premature Ageing
HUTCHINSON GUILFORD PROGERIA
 Male pattern baldness
 Cataracts
 Life span :10 yrs.
 Mutation in LMNA gene (codes for protein Laminin A)
 Defective precursor (PROGERIN)
 Interferes with organisation of nuclear heterochromatin
which regulates expression of various genes

31. Disorders of Premature Ageing
ATAXIA TELENGIECTASIA
 Manifestation of ageing at increased rate.
 Mutation in gene encoding for protein involved in repairing double
stranded breaks in DNA.

32. Premature Ageing Disorders
DOWN’S SYNDROME
 Patients generally age more rapidly.
 Their fibroblasts are capable of fewer cell divisions in culture than those
from age matched controls.
 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

35. Age related Diseases

38. SENESCENCE –POSITIVE 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.

39. THANK YOU