This presentation provides an overview of Cell senescence, Aging, Theories of Aging,principle of senescence, Mechanism of action, Factors, Diseases caused due to this action, Senescence and cancer, Insulin signalling cascade, Telomere shortening.

1. Senescence

2. Aging
 Aging can be defined as the time-related deterioration of the physiological functions
necessary for survival and fertility.
 The aging process has two major facets . The first is simply how long an organism
lives; the second concerns the physiological deterioration, or senescence, that
characterizes old age.

3. THEORIES OF AGING
Traditionally aging was explained two theories
 Programmed theories imply that aging is regulated by biological clocks
operating throughout the life span. This regulation would depend on changes in
gene expression that affect the systems responsible for maintenance, repair and
defense responses.
 Stochastic theories blame environmental impacts on living organisms that induce
cumulative damage at various levels as the cause of aging, examples which range
from damage to deoxyribonucleic acid (DNA), damage to tissues and cells by
oxygen radicals (free radicals), and cross-linking.

4. Other theories
 Molecular Gene Theory
 Codon restriction
 Somatic mutation
 Gene regulation
 Cellular theory
 Free radical theory
 Wear and tear theory
 Apoptosis
 Senescence
 System theory
 Rate of living theory
 Neuro endocrine theory
 Immunologic theory
 Evolutionary theory
 Disposable soma
 Antagonistic pleiotropy
 Mutation accumulation

5. WHAT IS SENESCENCE ?
 The process by which a cell loses its ability to divide, grow, and function. This loss of
function ultimately ends in death.
 In terms of cancer, it is the response of normal cells to potentially cancer-causing
events.
 It is a strictly degenerative process and has no positive features.
 It is characterized by the declining ability to respond to stress, increasing homeostatic
imbalance and increased risk of aging-associated diseases.
 Senescent cells secrete many inflammatory cytokines (e.g., IL6, IL8), growth factors
(e.g., PDGF), proteases (e.g., MMPs)

6. The Hayflick’s paradigm
 Hayflick limit or Hayflick phenomenon is the number of times a normal human cell
population will divide until cell division stops.

7. Factors responsible for senescence

8. Senescent cells:
Many characteristics change
Irreversible
Growth
Arrest
Resistance
to
Apoptosis
Altered
Function/Gene
Expression

9. Senescent Cells Accumulate In Vivo
With Increasing Age,
 skin, retina, liver, spleen, aorta, kidney, etc.
 Venous ulcers
 Atherosclerotic plaques
 Arthritic joints
 Benign prostatic hyperplasia
 Pre-neoplastic lesions

10. Genes Responsible for Senescence
 Klotho gene : responsible for down regulation of insulin signaling and
causes progeria.
 p53 : important regulator of cell division, stops cell cycle causing cell
senescence, provides protection against cancer, “guardian of the genome”.
 sirtuin gene : encode histone deacetylation enzymes and blocks
chromosomal rearrangement, sirtuin proteins prevent aging.

11. According to the
GenAge database of
aging-related genes there
are over 700 genes
associated with aging
in model organisms

12. Senescence morphology
 Senescent cells become flattened, enlarged and have increased β-galactosidase
activity
 Increased size of nucleus and nucleoli
 Increased number of multinucleated cells
 Increased number of lysosomes, Golgi and cytoplasmic microfilaments
'Young'
Pre-senescent
'Aged'
Senescent

13. Markers of a senescent cell
 p16 expression
 Heterochromatic foci damage
 Telomeric-DNA damage
 DNA damage foci
Human skin,
stained for SA-Bgal
Dimri et al., Proc Natl Acad Sci USA, 1995

14. Senescence and insulin signaling cascade

15. Telomers and Senescence
Telomere shortening causes cell senescence
 Somatic cells usually lack telomerase activity, which means that telomeres shorten
with each cell division.
 cells may go into crisis as the result of reaching zero telomere length.
 Reactivation of telomerase enables cells to survive crisis and to become immortal.
 Eroded telomeres generate a persistent DNA damage response (DDR), which initiates
and maintains the senescence growth arrest .
 This in turn activates the p53/p21 pathway.

17. Telomeres shorten with age
(Harley, 1990)

18. In most somatic tissues, telomerase is expressed at very
low levels or not at all -- as cells divide, telomeres shorten
Short telomeres signal cells to senesce (stop dividing)

19. Oxidative stress and Senescence
 Oxidative metabolism produces highly reactive free radicals that subsequently damage protein
and DNA.
 Oxygen free radicals generated cause cumulative oxidative damage, resulting in structural
degeneration, apoptosis, functional decline, and age-related diseases.
Evidence from model organisms
 Superoxide dismutase (SOD) transgenes can extend the life span of Drosophila.
 peroxidase activity can extend C. elegans life span.
 Catalase activity increases lifespan of C. elegans

21. Cell senescence and cancer
 Cellular senescence is an important tumour suppressor mechanism.
 The senescence response may be an example of evolutionary antagonistic pleiotropy.
 The rationale for antagonistic pleiotropy rests on the fact that most organisms evolve in
environments that are replete with fatal extrinsic hazards.
 The age-related increase in senescent cells occurs in mitotically competent tissues, which, of
course, are those that give rise to cancer

22. Short/dysfunctional
telomeres
(REPLICATIVE SENESCENCE)
DNA
Damage
Oncogenes
Chromatin
Instability
Supraphysiological
Mitogenic/
Stress Signals
Cellular Senescence Induced by Many
(Cancer-Causing) Stimuli
Irreversible
arrest of
cell
proliferation

23.  Inactivation of tumor suppressor genes encoding- p53 and pRB proteins =
most common.
 p53 and pRB proteins – control expression of other genes, halt cell cycle
progression in response to inducers of senescence, respond to senescent
signals, allow normal cells to sense
 Mutations that dampen cellular senescence greatly increase susceptibility
to cancer

24. The presence of telomerase in cancer cells allows them to
maintain telomere length while they proliferate

26. Progeria
 Progeria is a premature aging syndrome in humans that appears to be caused by
mutations in DNA repair enzyme
 In humans, Hutchinson-Gilford progeria is a rapid-aging syndrome;
 children born with this condition age rapidly, dying (usually of heart failure) as
early as 12 years of age.
 Hutchinson-Gilford progeria is the result of a dominant mutation in the gene that
encodes lamin A, a nuclear membrane protein, and these same mutations can be
seen in age-related senescence
 p53 can be activated by the absence of lamin A, thereby suggesting a mechanism
for Hutchinson-Gifford progeria

27. Symptoms
All symptoms are the characteristics of the human senescent phenotype.
 skin with age spots,
 resorbed bone mass,
 hair loss, and
 arteriosclerosis