Biochemistry of Aging PDF

BIOCHEMISTRY OF AGING Dr. A.Z. LAWAL, Medical Biochemistry, College Of Medicine, LAUTECH, Ogbomoso. Outline Overview Genetic basis Environmental and Epigenetic Longevity Overview Extremely complex and multifactorial process Characterized by gradual deterioration...

BIOCHEMISTRY OF AGING Dr. A.Z. LAWAL, Medical Biochemistry, College Of Medicine, LAUTECH, Ogbomoso. Outline Overview Genetic basis Environmental and Epigenetic Longevity Overview Extremely complex and multifactorial process Characterized by gradual deterioration in cells functions Major risk factors for human pathologies including cancer, CVS disorders and neurodegenerative diseases Rate of aging is controlled to some extent by genetic pathways and biochemical processes conserved in evolution The signs of aging start to appear after maturity Facets of Aging There are two facets of Aging Length of time Senescence ❖ Aging and senescence have both genetic and environmental components Genetic Basis The species-specific life span appears to be determined by genes that affect a trade-off between early growth, reproduction and somatic maintenance Molecular evidence indicate that certain genetic components of longevity are conserved between species e.g flies, worms, mammals and even yeast all appear to use the set of genes to promote survival and longevity ❖Genes encoding DNA repairs protein Two sets of genes are involved in aging and it’s prevention, both conserved between phyla and kingdoms of organisms: Genes encoding DNA repair enzymes Genes encoding proteins involved in the insulin signally pathway Species whose cells have more efficients DNA repair enzymes live longer. Certain premature aging syndromes (progerias) in human appear to be caused by mutations in such DNA repair enzymes  The protein p53 : ▪ One of the most important regulator of cell division often called the ‘’guardian of the genome’’ because of its ability to block cancers in several ways ▪ It can stop the cell cycle leading to cellular senescence in rapidly dividing cells ▪ Instruct the bax genes to initiate cellular apoptosis and activate DNA repair enzymes ▪ In most cell, p53 is bound to another protein that keeps it inactive  Ultralviolent radiation, oxidative stress and other factors that cause DNA damage will also separate and activate p53 P53 can be activated by the absence of lamin A thereby suggesting a mechanisms for hutchinson-gifford progeria. The suppression of signaling by insulin and insulin-like growth factor is one of the ways life span can be extended in many species ❖ Down regulation of insulin signaling pathway leads to: Decreasing mitochondria electron transport and sensitivity to ROS Increases the production of enzymes that prevent oxidative damage as well as DNA repair Increases fertility Environmental Basis People in 1900 did not have the luxury of dying of heart attacks or cancers, because this condition are most likely to affect people over 50years, rather people died from microbial and viral infection Thus, the phenomenal of senescence and diseases of aging are much more common today than they were a century ago Few people exhibits the general senescent phenotype such as grey hair, sagging, wrinkling skin, stiff joint, osteoporosis, loss of muscle fiber and muscular strength, memory loss, eye sight deterioration and slowed sexual responsiveness  Oxidative stress–induced protein and DNA damage Non infectious chronic inflammation Alterations in fatty acid metabolism Accumulation of end products of metabolism Alterations in neuroendocrine systems loss of post-mitotic cells (↓ neurons, muscle cells)  Aging theories: Free radical theory (Oxidative/Mitochondrial theory of aging): o Oxygen consumption, production of ATP by mitochondria and free-radical production are linked processes o Denham Harman propose that enhanced and unopposed metabolic-driven oxidative stress has a major role in diverse chronic age-related diseases o Increases in ROS accompany aging leading to functional alterations, pathological conditions, and even death o Organisms age due to the accumulation of free radical damage in the cell o Aged mammals has high quantities of oxidized lipids/proteins as well as damaged/mutated DNA, particularly in the mitochondrial genome o Increased regeneration of reducing agents and ATP can improve the recycling of antioxidants and assist the antioxidant defence system o On the other hand, enhanced mitochondrial activity may increase the production of superoxide, thereby aggravating the oxidative stress and further burdening the antioxidant defence system o The mitochondria are the major source of toxic oxidants, which have the potential of reacting with and destroying cell constituents and which accumulate with age o Thus, mtDNA is more vulnerable to attack by ROS o The result of this destructive activity is ↓energy production and a body that more readily displays signs of age (e.g., wrinkled skin, production of lower energy levels) o Accumulation of damage decreases the cell's ability to generate ATP, so that cells, tissues, and individuals function less well o The gradual loss of energy experienced with age is paralleled by a decrease in a number of mitochondria per cell, as well as energy producing efficiency of remaining mitochondria ❖ Major effect of mitochondria dysfunction includes: Inappropriately high generation of ROS PROTON leakage ↓ ATP production in relation to electron input from metabolism ❖ Leaked ROS and protons cause damage to a wide range of macromolecules, including enzymes, nucleic acids and membrane lipids within and beyond mitochondria, and thus are consistent with the inflammation theory of aging as being proximal events triggering the production of pro-inflammatory cytokines ❖ vicious cycle theory Free radical damage to mitochondrial DNA leads to mitochondria that produce more superoxide Most damaged mitochondria are degraded by autophagy, whereas the less defective mitochondria (which produce less ATP as well as less superoxide) remain to reproduce themselves The efficiency of autophagy to consume malfunctioning mitochondria declines with age, resulting in more mitochondria producing higher levels of superoxide Mitochondria of older organisms are fewer in number, larger in size and less efficient (produce less energy and more superoxide)  Free radicals could also be involved in signalling responses, which subsequently stimulate pathways related to cell senescence and death, and in pro-inflammatory gene expression This inflammatory cascade is more active during aging and has been linked with age associated pathologies, like cancer, cardiovascular diseases, arthritis, and neurodegenerative diseases  Other theories of aging ❖Telomere shortening hypothesis (Replicative senescence or Hayflick limit): Shortened telomeres activate a mechanism that prevents cell division it cannot explain the aging of the non-dividing cells, e.g. neurons and muscle cells, thus cannot explain the aging process in all the cells of an organism ❖The Reproductive-cell cycle theory: Aging is regulated by reproductive hormones, which act in an antagonistic pleiotropic manner through cell cycle signaling  Promotes growth and development early in life in order to achieve reproduction Later in life, in a futile attempt to maintain reproduction, become dysregulated and drive senescence ❖The Wear and tear theory of aging: Changes associated with aging result from damage by chance that accumulates over time Describe aging as an accumulation of damage and garbage that eventually overwhelms our ability to function ❖ Error accumulation and Accumulative waste theories: Chance events that escape proofreading mechanisms of genetic code build-up of cell waste products in time because of defective repair-removal processes The process of aging derives from imperfect clearance of oxidatively damaged, relatively indigestible material, the accumulation of which further hinders cellular catabolic and anabolic functions (e.g. accumulation of lipofuscin in lysosomes) ❖The programmed theories (e.g. aging clock theory): Propose a time-switch in our bodies that controls not only our process of development but also triggers our self-destruction The shortening of telomeres would provide such a clock in rapidly dividing cells ❖The Autoimmune theory of aging: Aging results from an increase in antibodies that attack the body's tissues ❖Mitohormesis theory of aging: “hormesis effects”. It describes beneficial actions resulting from the response of an organism to a low-intensity stressor ❖ Evolutionary theory of aging: Based on life history theory Constituted of a set of ideas that themselves require further elaboration and validation The Role of Oxidative Stress on the General Aging Process Oxidative damage is a result of the intrinsic and extrinsic ROS formation factors. The most important endogenous sources of oxidants are: ▪ Mitochondrial electron transport chain ▪ Nitric oxide synthase reaction Non-mitochondrial sources: ▪ Fenton reaction, ▪ Reactions involving cytochromes P450 in microsomes, ▪ Peroxisomal beta - oxidation ▪ Respiratory burst of phagocytic cells ❖ Causes of increased free-radical production include : ❑ Endogenous ▪ Elevation in O2 concentration ▪ Increased mitochondrial leakage ▪ Inflammation ▪ Increased respiration ❑Exogenous ▪ Environment (pollution, pesticides, radiation, etc.) ▪ Smoking ▪ Poor nutrition ▪ Disorders and chronic diseases ▪ Chronic inflammation ▪ Lifestyle ▪ Strenuous excercise ▪ Psychological and emotional stress ❖Causes of decreased antioxidant defense include: ▪ Reduced activity of endogenous antioxidative enzymes ▪ Reduced biokinetics of antioxidant metabolism ▪ Reduced intake of antioxidants ▪ Reduced bioabsorption of antioxidants  Oxidative stress is caused mainly by: ▪ Mutation or reduced activity of enzymes (catalase, SOD, glutathione peroxidase) ▪ Decreased intake of exogenous antioxidants from food ▪ Increased metal ion intake (e.g., Fe, Cu, Cr) ▪ Easiliy peroxidized amino acids (e.g., lysine) ▪ Increased triplet oxigen (3O2) concentration ▪ increased physical activity of an untrained individual ▪ ROS from ionizing radiation, air pollution, smoking ▪ Chronic inflammation Promoting longevity ❖ Several interacting agent may promote longevity. This include: Calorie restriction Protection against oxidative stress Factors activated by a suppressed insulin pathway Assignment Defenses against ROS ▪ Primary ▪ Secondary