Biology of Aging • What is aging? – definition of aging • Why do we age? – theories of aging • How do we age? – mechanism of aging • Is aging same across the tree of life? • Can we cure aging? What is aging? Aging: the time-sequential deterioration that occurs in most animals including weakness, increased susceptibility to disease and adverse environmental conditions, loss of mobility and agility, and age-related physiological changes. Aging is usually understood to include reductions in reproductive capacity. Term senescence is sometimes used to indicate the deteriorating effects of aging as opposed to the simple passage of time. Aging: all of the time-dependent changes that occur in the molecules, cells and tissues of an organism. Life expectancy (longevity) is a statistical measure of how long a person or organism may live. Mortality in the United States in 1999 as a function of age PROBABILIY OF DEATH = The chance of dying any given year. Gompertz curve Aging: drop in survival probability and fertility with advancing adult age. Aging: the decline of cell/organ/organisms peak function that continues until its failure or death. Cutler & Mattson, Ag. Res. Rev. (2006) Why do we age? Features of life • life is cellular • reproduction/replication • homeostasis • metabolism • selfassembly • ability to harvest energy • life has history: ability to evolve 7 How life defies entropy? In the long run, nothing escapes the Second Law of Thermodynamics. The pull of entropy is relentless. Everything decays. Disorder always increases. “The ultimate purpose of life, mind, and human striving: to deploy energy and information to fight back the tide of entropy and carve out refuges of beneficial order.” —Steven Pinker 8 Life is very good at harvesting energy from its surroundings Life has history: Back to One LUCA: last universal common ancestor 9 Finch & Austad, Exp. Gerant. (2001) Ageing is determined genetically Theories of aging Weismann’s theory of programmed death: “Programmed death” was a genetically programmed, evolved characteristic, (an adaptation), and that this characteristic had evolved through natural selection because it conveyed a benefit to the species even though it had a negative effect on individual fitness. Is aging adaptive characteristic evolved by natural selection or is it instead some fundamental property of life or some fundamental physical limitation? Accumulation damage theories: The laws of entropy say that everything goes from an ordered to a less ordered state as time passes. Wouldn’t aging be an example of entropy? •Aging is not a defect; it is a feature that has a purpose. •Aging is a defect; it is a fundamental property of life or unavoidable side effect of necessary process. “Unorthodox” theories of aging advocate the hypothesis that aging is a evolved adaptation that has its purpose. These “adaptive” theories are all based on the idea that the theory of natural selection, although correct, is not complete and that therefore exceptions, additions, or expansions are possible. Group (kin) selection: characteristics beneficial to a group could be selected (parallel with altruism). Evolvability: capacity for evolution. According to Darwin, organisms evolve incrementally in tiny steps. Each generation of an evolving species is only minutely more adapted than the previous generation. A species with a shorter life span would accumulate such incremental improvements in adaptation more rapidly and therefore would have an advantage over a species with a longer life span. A species needs a life span sufficient to fully develop, breed at least once, and nurture and protect progeny (if applicable). A longer life span would have a progressively smaller survival and reproduction advantage and a progressively larger evolvability disadvantage. The challenge effect: Animals have to pass a test in order to breed. As animals become older and weaker, they are less able to pass the challenge. However, and exceptional animal possessing a beneficial trait pass the ritual despite of aging. Goldsmith, Evolution of aging (2004) Darwin’s dilemma: Since longevity was of value increasing the survival time and breeding opportunity of any organism, wouldn't natural selection (if true) result in ever-increasing longevity? Wouldn’t aging, since it was obviously adverse to fitness be “selected out” by the process of natural selection? In other words, Darwin’s theory predicts that animals and humans should not age (if it is indeed “genetically programmed mechanism”). Problem: how genes for aging can be selected for? • Aging genes should be ignored by selection as their effect is manifested mostly post-reproductively • Aging rarely occurs in nature Evolutionary theories of aging combine natural selection with “accumulation of damage”. The factors that cause aging are genetically transmitted but not “genetically programmed”. Medawar’s mutation accumulation theory: Williams’ antagonistic pleiotropy theory: proposed that aging was caused by the combined effect of many pleiotropic genes that each had a beneficial effect in an animal’s youth but had an adverse side effect in older age. Williams predicted that species with younger age of sexual maturity and more vigorous reproduction traits would tend to have shorter life spans. Medawar proposed that aging was caused by random mutations causing adverse aging characteristics. In effect, aging is caused by an assortment of genetic diseases, each of which has adverse symptoms only at advanced ages. The adverse mutations are only gradually selected out because of their minor negative effect on individual fitness but are replaced by new, random mutation, aging characteristics at a rate that is in equilibrium with the rate at which old adverse characteristics are selected out. Disposable soma theory: Organisms only have a limited amount of energy that has to be divided between reproductive activities and the maintenance of the non-reproductive aspects of the organism (soma). Aging is the result of natural degrading processes that result in accumulation of damage but the damage can be repaired by the organism at the expense of reproductive effort. Aging is trade off How do we age? (Mechanisms of aging) Reactive Oxygen Species (Oxydative damage theory of aging) Balaban et al., Cell 2005 Cytochrom chain Superoxide is also produced in phagocytes by the NADPH oxydase and used to kill invading pathogenes. Aging and molecular chaperones Chaperones are ubiquitous, highly conserved proteins, either assisting in the folding of newly synthesized or damaged proteins in an ATP-dependent active process or working in an ATPindependent passive mode sequestering damaged proteins for future refolding or digestion. In an 80-year old human, half of all proteins may become oxidized. Performance of chaperones may decrease with aging. Soti & Csermely, Exp. Geront. (2003) Crude estimates of the number of DNA-damage events in single human cell range from 104 - 106 per day, which thus requires 1016 - 1018 repair events in adult human (1012 cells) per day. Robust DNA repair Damage to DNA Manifestations of aging Rando, Nature (2006) Proliferation of tissue stem cells in adult animals is mainly responsible for the maintenance of diverse tissues. Stem cells and cell intrinsic mechanisms of aging Stem cells Rando, Nature (2006) Cell intrinsic mechanisms of aging: cellular senescence Cell senescence and aging Hayflick limit: Human fetal fibroblast have only finite replicative capacity in vitro – evidance for cellular aging in vitro (Hayflick, Exp. Cell Res. 1965). The major features of the cells undergoing senescence: • Irreversible arrest of cell division • Resistance to apoptosis • Secretion of variety of molecules that can drastically alter tissue environment Animals must continuously substitute for the loss of cells, such as granulocytes, keratinocytes, hepatocytes and erytrocytes to maintain organismal homeostasis. Increased cell senescence in populations of adult stem cells can impair tissue regeneration and contribute to organismal aging. Figure 10.13b The Biology of Cancer (© Garland Science 2007) Figure 10.31 The Biology of Cancer (© Garland Science 2007) Telomerase deficient mouse exhibits symptoms of premature aging Telomerase extends replicative lifespan of human cells b-galactosidase assay after 60 PD Bodnar et al., Science (1998) Tomas-Loba et al., Cell (2008) The cellular senescence and antagonistic pleiotropy Non-cell autonomous mechanisms of aging Pacific salmon: extreme increase of stress hormone cortisol after the first (and only) spawning leads to degeneration of number of glands and organs which in turn causes death by multiple organ failure. Cell non-autonomous mechanisms are usually coupled with reproduction or energy metabolism. Endocrine system appears to be the major modulator of aging and lifespan in animal. The degree to which endocrine system influences aging is hormone- and species specific (e.g. estrogen in human has some antiaging effects, prolactins and gonadotropins may promote progression of some aging related diseases). Regulation of aging by endocrine system sch9 chico GHR/BP null mice Longo & Finch, Science (2003) Caloric restriction Caloric restriction can in rodents increase life span by 35% and also result in a lower incidence of tumors, kidney disease, vascular calcification and chronic pneumonia. In times of famine, the immediate prospects for successful reproduction and for survival of vulnerable offspring are diminished, while the reward for surviving through to the end of the famine is an opportunity to deliver offspring into the newly abundant but depopulated world that emerges. Fontana, Science (2010) Naked mole-rat • The longest living rodent (over 30 years, average for other species 4 years) • Unusual resitence to cancer • Tissues accumulate high-molecular weight hyaluronan Tian et al, Nature (2013) • Cells with KO of hyaluronan synthase become susceptibel to malignant transforamtion • Decrese in mortality and constant fertility with age; physiologicaly young at advanced age Greenland shark – an individual tha could be up to 512 old Are there immortal animals? Niellsen et al, Science (2016) Yeast replicative lifespan: number of cell divisions an individual cell can undergo before dying. Yeast chronological lifespan: a length of time a population of cells remains viable in non dividing state after nutrient deprivation. Unicellular organisms: aging in yeast These degenerative activities occur concomitantly with a massive remobilization of the hydrolized molecules to the growing parts of plants, such as young leaves, developing seeds, and fruits. Leaf senescence is a programm Gan & Amasino, Science (1995) Reversing leaf senescence The term senescence is used in a specialized way by plant scientists: it is highly regulated physiological process that allows nutrient remobilization and ends up in the death of cell, organ or plant, but it is not by itself aging (leaf senescence in trees is a recurrent process). Leaf senescence vs organismal aging Life forms in perennials: Perennials: plants that live for more than two years 1. woody perennials 2. herbaceous perennials 3. clonal, creeping perennials (clover, prairie grass) bristlecone pine ~5000 years (germinated 3050 BC) Larrea tridentata ~11000 years Borderea pyrenaica ~300 years Perenial plants: some of the longest living organisms on this planet Munne-Bosch, Crit Rev Plant Sci (2007) Larrea tridentata ~11700 years old clone in Mojave desert The „King clone” Vasek, Am J Bot (1980) Aging is a fate that probably awaits all living organisms: it is just that plants are organized so that they are not there when it happens. - Howard Thomas What makes plants special? • Indeterminate growth • Modular development • No separation of germline from soma Plant growth is driven by cell division in meristems shoot apical meristem root meristem Tissue organization and protection of the stem cell genome Organization of stem cells in gastrointestinal crypts of the small intestine enterocytes (~3500) Stratification of plant meristems may decrese mutation by protecting stem cells from excessive proliferation trembling aspen There may not be a universal cause of aging valid for all organisms. Can we cure aging? The Fountain of Youth, a 1546 painting by Lucas Cranach the Elder.