Cellular ageing

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 Condensation of chromatin and nuclear shrinkage Degeneration of cytoplasmic organelles Insufficient production of some enzymes Accumulation of ageing pigments and free radicals Change in level of hormones Low antibody production and weak immune mechanism 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

14. 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

15. 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

16. 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

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

18. 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

19. 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

20. 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

21. 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

22. 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

23. 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

24. 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

25. 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

26. 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

27. 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

28. 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)

29. 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

30. 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) 

31. 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