Describes the process of ageing in cells, factors affecting cells like telomere, free radicals, oxidative stress, DNA damage, environmental factors, proteostasis, mitochondrial disfunction etc are described

1. Cellular aging
Radhakrishna G Pillai
Department of Life Sciences
University of Calicut

2. CELLULAR AGING
• Ability to respond to stress decline
• Homeostatic imbalance increase
• Progressive deterioration of structural properties
• Decrease in functional efficiencies of cell and
• Loss of restorative and reparative powers
• What cause aging of cells?
• Prolonged and constant use and Wear and Tear cause aging
• Exposure to external factors that cause accumulation of cellular
and molecular damage
• Life span vary from cell to cell

3. Why study aging?
• Proper knowledge: help to achieve lifespan extension in human
• Know the cellular programs responsible for aging
•Knowledge on the effect of dysregulation help to find solution
• Protein aggregation, autophagy, proteostasis etc involved in aging
• Role of such processes in human aging and diseases like Alzheimer’s
and Parkinson’s can be determined
• Increase the quality of life of aging people at high risk of these
diseases

4. Interplay of processes controlling aging
•Cellular health is controlled at various points in the cell;
• in the nucleus through
• chromosome structure/organization
• transcriptional regulation and nuclear export/import
• protein translation and quality control
• autophagic recycling of organelles
• maintenance of cytoskeletal structure and
•maintenance of the extracellular matrix and
extracellular signaling
•Each regulatory system receives information from every other
system, resulting in an intricate interplay of regulation
controlling the aging of the cell

5. CELLULAR CHANGES
o Condensation of chromatin and nuclear shrinkage
o Degeneration of cytoplasmic organelles
oInsufficient production of some enzymes
o Accumulation of ageing pigments and free radicals
o Change in level of hormones
o Low antibody production and weak immune mechanism
o Low rate of cell division

6. • Traditionally aging explained by two theories
• Programmed aging
– Imply that aging is regulated by biological clocks
operating throughout the life span
– This depend on changes in gene expression that
affect the systems responsible for maintenance,
repair and defense responses
Theories of ageing

7. • Stochastic theories
– environmental impacts on living organisms that
induce cumulative damage at various levels as
the cause of aging
– eg. damage to DNA, damage to tissues and cells
by oxygen radicals (free radicals)
Theories of ageing

8. Recent theories of aging
• Molecular Gene Theory
– Codon restriction
– Somatic mutation
– Gene regulation
• Cellular theory
– Free radical theory
– Wear and tear theory
– Immunological/autoimmune
– Collagen cross linking
– Apoptosis
– Senescence
– telomere loss and cellular stress

9. Mitochondrial theory of aging
• Mitochondrial dysfunction due to;
– Oxidative stress
– Lipid peroxidation
– lipid hydroperoxide-derived DNA adduct
formation
– Mitochondrial DNA damage/deletion
– Oxidation of proteins
– Decrease in repair system

10. Free Radical theory
• Free radicals are byproducts of metabolism--can increase
as a result of environmental pollutants
• Cause various diseases in body like diabetes, plaque
formation in Alzheimer’s disease
• When they accumulate, they damage cell membrane,
decreasing its efficiency
• The body produces antioxidants that scavenge the free radicals
• Administration of antioxidants : beneficial in oxidative stress

11. Cross-Linkage Theory
• Some proteins in the body
become cross-linked, thereby
not allowing for normal
metabolic activities
• Waste products accumulate
• Tissues do not function at
optimal efficiency

12. Wear & Tear Theory
• Proposed first in 1882
• Continued use cause wear and tear in
cells like a machine
• Exercise actually makes cell more
functional

13. Programmed (Hayflick Limit) Theory
• Proposed in 1961
• Based on lab experiments on fetal fibroblastic cells
and their reproductive capabilities
• Cells can only reproduce themselves a limited
number of times
• Life expectancies are seen as preprogrammed
within a species-specific range

15. Mitochondria
• Power supply to cells
• Free radicals produced as bye products
• Change in mitochondrial membrane potential
• Somatic mitochondrial DNA mutations and
respiratory chain dysfunction accompany
normal aging
• Insulin/IGF-1 signaling underlie the central
role of mitochondria in the aging process

16. Free radicals
• Free radicals are normally detoxified by
internal mechanisms in cell
• Higher levels of free radicals: body
system fail to detoxify
• Damage cells : oxidative damage to proteins
and DNA
• Damage to mitochondrial systems: decrease
in energy release from mitochondria
• Induce apoptosis

17. Cell cycle regulation
• Different proteins
involved
– Cyclins, mitogen
activated protein (MAP)
kinases etc
• Protein damage: cell
cycle regulation in
disorder
• Disorders in cell cycle
regulation: cellular
aging or malignancy

18. Gerento genes
• Genes related to aging
• When they are damaged: speed up aging
• Genetic polymorphism related to aging
identified

19. Telomere length
• Telomere: terminal part of eukaryotic chromosome
• Also called molecular clock
• TTAGGG tandem repeats at the ends of mammalian
chromosomes
• Protect chromosomes from damage caused by shortening
(due to end-replication problems on the lagging strand and
oxidative damage at each replicative cycle)
• Attrition of telomere with each division of somatic cells in
culture
• Telomere length is an indicator of cell’s replicative history
and the potential to replicate

20. Telomere length
• Increased stress in humans leads to increased telomere shortening
• In human beings, telomere length is heritable
• It is relatively short and highly variable
• In replicating somatic cells; inversely related with age
• Humans: long lifespan of humans and short telomeres
• Reduction in telomere length: determine aging at the cellular level
• Mammalian cell cultures enter senescence after 40–60 divisions,
known as the Hayflick limit or replicative senescence

21. Transcriptional regulation of aging
• Most cellular processes that affect longevity are
regulated at the transcriptional level through highly
conserved signaling pathways
• Transcriptional regulation coordinate the activation of
many genes to extend lifespan
• The Nrf/SKN-1 transcription factor mediates longevity
• SKN-1/Nrf transcription factors regulate diverse
biological processes essentially stress defense,
detoxification, and longevity

22. Nuclear trafficking
• The eukaryotic nuclear pore complex (NPC):
– one of the most complex molecular devices
– serves essential role in exporting messages and proteins
into and out of the nucleus and
– critical to many aspects of cellular regulation and health
– including tumor suppression

23. Nuclear trafficking
• mRNA is shuttled to the cytoplasm through the NPC
• Nuclear trafficking decreases with cellular senescence,
leading to hypo responsiveness to cellular stresses
• NPC proteins are long lived, rendering them susceptible
to age-related damage
• Progressive degradation of nucleoporins further
contributes to aging through leaking of proteins and
messages

24. Organisation of Nucleus
• Organization inside the nucleus is also important for cellular
health
• Incorrect organization of lamins at the nuclear envelope cause
laminopathies, including “premature-aging” diseases
• Laminopathies render DNA sensitive to damaging agents, causing
higher rates of breaks, relocations, and aneuploidies
• Damage in lamin results in increased sensitivity to reactive oxygen
species (ROS), leading to oxidative damage to cells
• Altered nuclear architectures observed in patients with
cardiomyopathies and in aged and damaged stem cells

25. Proteostasis
• Maintenance of protein quality, or proteostasis, is critical
for the health and longevity of the cell
• Ensures a supply of high-quality protein
– cull misfolded and damaged proteins from the cellular pool and
– replace them with newly formed proteins
• Molecular chaperones direct amino acid chains to correct
folding and direct misfolded proteins to degradation
pathways and refold misfolded proteins
• Increased proteostasis is necessary for the longevity
of many cells

26. Autophagy
•Cell organelles are consumed by the cell through autophagy
•Damaged organelle encased in double membrane forming
autophagosome, which traffics to the lysosome & broken
down
•Autophagy is required for longevity in many species -
inhibition accelerates aging
•Autophagic clearing of damaged proteins, protein aggregates,
organelles, lipids etc is required to provide new raw material
for a healthy cell

27. Cytoskeletal integrity
• The CS is critical in maintaining cell shape and
integrity, and its dysregulation is an indicator of cellular aging
• ROS, ischemia, ultraviolet treatment, toxins etc can lead to
cytoskeletal stress, which activates apoptosis
• Actin filament cross-linking protein is a biomarker of aging
• The apolipoprotein E4 (apoE4) is a risk indicator of Alzheimer’s
• ApoE4 is proteolyzed in neurons, forming toxic fragments that
interact with the actin cytoskeleton hastening cell aging and
apoptosis

28. Cell membrane and extracellular matrix
• The extracellular matrix (ECM) is an important contributor
to health and longevity and is also an indicator of the
health inside the cell
• Collagen expression in C. elegans declines with age and
regulation of specific collagens help lifespan extension
• Aging humans also experience glycosylation and other
proteomic damage to the ECM proteins
• Proteomic damage is accelerated in type 2 diabetes
patients due to buildup of oxidative damage products and
ROS

29. Replicative aging and senescence
• Cells experience aging linked to the
number of divisions they have
undergone (replicative aging)
• S. cerevisiae reproduces by budding a
new cell off of the mother cell and can
undergo ∼26 such divisions before the
detrimental effects of age start
• The daughter cell is not limited by the
number of previous divisions of the
mother cell (due to renewal of its
replicative potential)

30. Replicative aging and senescence
• Disruption of TOR signaling, dietary restriction, and
change in intercellular pH – modify aging
• During replicative aging;
– oxidative damage products such as carbonylated
proteins and
– accumulated cellular damage build up in the yeast
mother cell
• These are retained by the mother cell, allowing the
newborn daughter cell to be born without this
hallmark of aging

31. Replicative aging
• Resetting of replicative potential has clear parallels in
mammalian and invertebrate gametogenesis
• Stem cells undergo asymmetric divisions that segregate
new mitochondria to the daughter cell, affecting their
ability to maintain “stemness”
• As cells age, they communicate their internal status—
DNA damage, oncogene activation and proteomic
dysregulation to their neighbours by the senescence-
associated secretory phenotype (SASP)

32. Senescence-associated secretory
phenotype (SASP)
• Particular SASP profiles vary based on cell type and
context
• Dysregulation of replicative lifespan is characteristic of
diseases of aging
• Stem cells maintain a balance between multipotency and
tumorogenicity by careful internal regulation and by
sensing external stimuli
• Aging and senescence plays an important role in limiting
the chance of errors that compromise the overall health of
the organism