Cellular Aging Pathways PDF

Cell Ageing Process Mol & Cell Biology MD105 Prof A. Stephanou  Objectives: Understand the aging process at the molecular and cellular level and its characteristics Understand the molecular and physiological aging process e.g IGF and p53 signaling pathways Association betwee...

Cell Ageing Process Mol & Cell Biology MD105 Prof A. Stephanou  Objectives: Understand the aging process at the molecular and cellular level and its characteristics Understand the molecular and physiological aging process e.g IGF and p53 signaling pathways Association between Telomeres and cellular aging What IS Aging? Aging is a biological process Aging is a PROCESS that converts a healthy, fit organism (for its environment) into one that is less healthy and fit Is There a Connection Between Organismal Aging and Cellular Aging ?? (biological clock)  AGING Epigenetics Reduced tissue/physiological function Increased susceptibility to disease (age-related diseases) Decreased resistance to stress (physical and psychological) Changes in the Plasma Membrane: Structural Changes lead to changes in permeability Less Fluid due to increase in saturated fatty acids  Nuclear Changes Chromatin becomes more condensed (increase cross-links) (disulfide bonds between histones) Implication: Damage to DNA less likely repaired Cells in culture will eventually stop growing (senescence) due to changes in factors that regulate the cell cycle.  Cytoplasmic Changes Increase volume with age Lipofuscin- (age pigment) found in non-dividing cells e.g. nerve and muscle Yellow - brown lipofuscin granules  Mitochondrial Changes Decrease number of folds (cristae) Decrease in number of mitochondria  Lysosomal Changes Decrease in activity leads to accumulation of cellular garbage e.g. lipofuscins Release of enzymes leads to cell death Pre-programmed Cell Death (apoptosis) Apoptosis vs. Necrosis Necrosis - external cause (trauma) random breaks in DNA Apoptosis- internal cause (cellular suicide) non-random 180 base fragments Apoptosis - natural developmental process e.g. interdigital tissue (webbing) neurons  Cellular “aging” = response to damage or stress Cell death Arrested cell growth (apoptosis) (cell senescence)  Cellular “aging” responses: YIN and YANG Good news! (prevents cancer) Bad news! (promotes aging) Evolution of Long-Lived Organisms Years LIFE SPAN Days/wks Min/hrs No Cancer Cancer Single-celled Multi-cellular, Multi-cellular, Post-mitotic + Post-mitotic Renewable tissues ORGANISMS CELL DIVISION IS RISKY!!  Cancer The bad news Cancer risk rises exponentially with age Fueled by (somatic) mutations Mutations caused by DNA damage, from endogenous and exogenous sources  Cancer The good news! Genes evolved to protect from cancer (tumor suppressor genes) Tumor suppressor genes cause damaged cells to die or arrest growth (undergo apoptosis or senescence)  Tumor suppression and aging: An evolutionary balancing act! Cancer Cellular protection aging  Senescence morphology Senescent cells become flattened, enlarged and have increased -galactosidase activity Increased size of nucleus and nucleoli Increased number of multinucleated cells Increased number of lysosomes, Golgi and cytoplasmic microfilaments  Cellular Senescence: Arrests Cell Growth In response to Potential Cancer-Causing Events Chromatin Stress/damage Irreversible Signals Instability arrest of cell growth DNA Damage Oncogenes Short/dysfunctional telomeres  What can molecules secreted by senescent/'aged' cells do? Disrupt normal tissue differentiation Example: milk production by mammary cells  Cellular senescence (cellular aging) 'Young' 'Aged' Presenescent Senescent MOLECULAR AND PHYSIOLOGICAL MECHANISMS OF AGING (1)Dietary restriction after adulthood reduces effects of aging & leads to increased lifespan, in lab animals (yeast, worms, Daphnia, Drosophila, mice, primates). Molecular basis of this effect is rapidly being uncovered (2) Insulin/IGF-1 signalling pathway genes are strongly implicated in aging effects - these genes regulate metabolism and stress responses, affect maintenance functions  Integrating molecular mechanisms with life- history theory (1) Insulin/IGF1 (‘growth’ hormones) pathway appears to strongly regulate tradeoffs between growth, maintenance -poor environment (eg dietary restriction) - increase maintenance (survival), reduce growth and/or reproduction -good environment - increase growth and/or reproduction, decrease maintenance (2) In lab animal studies, life-span extending mutations of insulin/IGF mutants do poorly & do not show evidence of long lives. The insulin-like pathway in Drosophila P P P dFOXO dFOXO Increased longevity? Does it control ageing?  Insulin/IGF-1 signalling and ageing in mammals! Worms, flies: One insulin/IGF-1 receptor Mammals: insulin receptor, IGF-1 receptor, insulin-receptor-like receptor…. Insulin receptor Mild reduction of function of IR gene: type 2 (non-insulin dependent) diabetes Insulin signalling promotes ageing? Unlikely? IGF-1, insulin-like growth factor 1 Anterior Growth pituitary hormone gland (GH) Liver The somatotropic IGF-1 axis Cell survival, growth Puberty, gonadal function Reduced adiposity  IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice Holzenberger (2002): Mice heterozygous for a deletion of the IGF-1 receptor gene Resistant to oxidative stress Increased mean lifespan (33% females, males not long lived) Oxidative stress (Holzenberger et al. Nature 2002) p53 gene, cancer risk, and aging in mice p53 alleles in this mouse strain: + = wild type - = loss of function m = mutation  Telomeres and Aging: Is there a connection?  What are telomeres? Telomeres are… – Repetitive DNA sequences at the ends of all human chromosomes – They contain thousands of repeats of the six- nucleotide sequence, TTAGGG – In humans there are 46 chromosomes and thus 92 telomeres (one at each end)  Telomerase and Senescence 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)  Telomerase and Cancer The presence of telomerase in cancer cells allows them to maintain telomere length while they proliferate  Short telomeres cause growth arrest via a checkpoint Sensed as DNA damage by the p53 checkpoint Stops Cell Division If the cells of a particular tumor still have p53, this works  Tumor cells often lose p53 Sensed as DNA damage by the p53 checkpoint Cell division continues without telomeres leading to chromosomal rearrangements This genomic instability can promote tumorigenesis  What do telomeres do? They protect the chromosomes. They separate one chromosome from another in the DNA sequence Without telomeres, the ends of the chromosomes would be "repaired", leading to chromosome fusion and massive genomic instability.  Telomere function, cont’. Telomeres are also thought to be the "clock" that regulates how many times an individual cell can divide. Telomeric sequences shorten each time the DNA replicates. Once the telomere shrinks to a certain level, the cell can no longer divide. Its metabolism slows down, it ages, and dies  Telomeres & Aging Healthy human cells are mortal because they can divide only a finite number of times, growing older each time they divide. Thus cells in an elderly person are much older than cells in an infant. It has been proposed that telomere shortening may be a molecular clock mechanism that counts the number of times a cell has divided and when telomeres are short, cellular senescence (growth arrest) occurs.  How Does Telomerase Work? In humans, telomerase is active in germ cells, in vitro immortalized cells, the vast majority of cancer cells and, possibly, in some stem cells. High telomerase activity exists in germ cells, stem cells, epidermal skin cells, follicular hair cells, and cancer cells. Some cells are immortal because their telomerase is switched on Examples of immortal cells: blood cells and cancer cells Cancer cells do not age because they produce telomerase, which keeps the telomere intact.  Human aging The Greek God Zeus granted Tithonus the gift of immortality, but not of perpetual youth, when requested by his wife Eos. Tithonus grew progressively ancient, and begged for death to overcome him Tennyson’s poem “Tithonus”: “Man comes and tills the field and lies beneath, And after many a summer dies the swan. Me only cruel immortality Consumes: I wither slowly in thine arms” Living longer without youthful vitality is not a good idea