Why we age: Insight into the cause of growing old

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A Better Understanding of the Mechanisms Surrounding Thymic Involution

The equilibrium between resources invested in longevity versus those for reproductive fitness determines life span Loison et al This antagonism between reproduction and longevity is supported by experiments in which the limitation of the reproduction by destroying germ line cells can extend life span in both Drosophila and Caenorhabditis elegans. More than theories have been proposed to explain the aging process Medvedev , but none has yet been generally accepted by gerontologists.

Neverthelss, the free radical theory of aging seems to be the one receiving the widest acceptance as a plausible explanation of the primary chemical reactions at the basis of the aging process De La Fuente The free radical theory of aging was first formulated in the Fifties by Harman who hypothesized a single common process, modifiable by genetic and environmental factors, in which the accumulation of endogenous oxygen radicals generated in cells could be responsible for the aging and death of all living beings Harman ; Finkel and Holbrook This theory was then revised in Harman when mitochondria were identified as responsible for the initiation of most of the free radical reactions related to the aging process.

It was also postulated that the life span is determined by the rate of free radical damage to the mitochondria. The increasing age-related oxidative stress seems to be a consequence of the imbalance between the free radical production and antioxidant defenses with a higher production of the former Sastre et al All organisms live in an environment that contains reactive oxygen species.

Mitochondrial respiration, the basis of energy production in all eukaryotes, generates reactive oxygen species by leaking intermediates from the electron transport chain Finkel and Holbrook The universal nature of oxidative free radicals, and possibly of the free radical theory of aging, is suggested by the presence of superoxide dismutase in all aerobic organisms and responsible for scavenging superoxide anions Finkel and Holbrook Moreover, cellular oxidative damage is indiscriminate. In fact, oxidative modifications have been shown to occur in of DNA, protein, and lipid molecules Weinert and Timiras Elevated levels of both oxidant-damaged DNA and protein have been found in aged organisms Beckman and Ames ; Shringarpure and Davies However, even if it is clear that the age-related accumulation of oxidative damage, it is not yet clear whether this process contributes to aging in all organisms.

The increased life span of transgenic flies expressing superoxide dismutase indicates that free radical-scavenging enzymes are sufficient to delay aging in Drosophila Tower Moreover, flies selected for increased longevity have elevated levels of superoxide dismutase and increased resistance to oxidative stress Arking et al It has also been demonstrated that long-lived mutant worms are also resistant to oxidative stress and show an age-dependent increase in superoxide dismutase and catalase activity Larsen The free radical theory of aging is divided into several hypotheses focusing on the exclusive role of particular organelles and types of damaged molecules in the aging process Weinert and Timiras For example, it has been hypothesized that mutations in mitochondrial DNA accelerate free radical damage by introducing altered enzyme components into the electron transport chain.

Faulty electron transport consequently results in elevated free radical leakage and ultimately more mitochondrial DNA mutation and exacerbated oxidant production. Another hypothesis argues that free radicals cause aging because of the accumulation of oxidized proteins in cells. The age-dependent reduction in the capacity of degradation of oxidized proteins may be responsible for the build-up of damaged, dysfunctional molecules in the cell Shringarpure and Davies This theory hypothesizes that the accumulation of genetic mutations in somatic cells represents the specific cause of senescence Beckman and Ames The identification of free radical reactions as promoters of the aging process implies that interventions aimed at limiting or inhibiting them should be able to reduce the rate of formation of aging changes with a consequent reduction of the aging rate and disease pathogenesis Harman In a normal situation, a balanced-equilibrium exists among these three elements.

Excess generation of free radicals may overwhelm natural cellular antioxidant defenses leading to lipid peroxidation and further contributing to muscle damage Bowles et al ; Meydani et al Even if antioxidant supplementation is receiving growing attention and is increasingly adopted in Western countries, supporting evidence is still scarce and equivocal. In fact, even if some epidemiological studies shown that dietary supplementation with vitamin E decreases the risk of cancer and cardiovascular disease, such observations are not universal Butler et al The only capability of reducing oxidative damage through antioxidant supplementation is limited.

Therefore, the longevity-extending potential of antioxidant supplementation in particular, vitamin E as the most studied one remains uncertain even in animal studies Anisimov The only robust finding that a pharmacological antioxidant can extend longevity has been reported by Melov and colleagues in an animal model in demonstrating that EUK, a compound with both catalase and superoxide dismutase activities, significantly extends longevity in nematodes. The age-related physiological decline seems to be due to the accumulation of defects in the several metabolic pathways. Looking for potential candidates to progressive accumulation of damage over a lifetime, it seems reasonable to exclude RNA, proteins and other cellular macromolecules with a rapid turned over.

For this main reason, studies exploring mechanisms of aging have always been focused on DNA. In mammalian cells, mitochondria and the nucleus are the only organelles possessing DNA. It appears obvious that the physiological integrity of the cell is strongly linked to the integrity of its genome. Mitochondrial DNA, in close proximity to the sites of oxygen radical production and unprotected by the histones that are associated with nuclear DNA, is a sensitive target for oxygen radical attack.

In fact, it has been estimated that the level of oxydatively oxidized bases in mitochondrial DNA is to fold higher than that in nuclear DNA Richter et al ; Ames Moreover, mitochondrial DNA encodes polypeptides of the electron transfer chain as well as components required for their synthesis. Therefore, any coding mutations in mitochondrial DNA will affect the entire electron transfer chain, potentially altering both the assembly and function of the products of numerous nuclear genes in electron transfer chain complexes.

Finally, defects in the electron transfer chain can have pleiotropic effects because affecting the entire cellular energetics Alexeyev et al It has been demonstrated by the Framingham Longevity Study of Coronary Heart Disease that longevity is more strongly associated with age of maternal death than that of paternal death, suggesting that mitochondrial DNA inheritance might play an important role in determining longevity Brand et al Even if the matter is still controversial Ross et al , several studies demonstrate that longevity is associated with specific mitochondrial DNA polymorphisms Ivanova et al ; Tanaka et al ; De Benedictis et al The mitochondrial theory of aging is often considered as an extension and refinement of the free radical theory Harman ; Miquel et al Mitochondrial DNA mutations accumulate progressively during life and are directly responsible for a measurable deficiency in cellular oxydative phosphorylation activity, leading to an enhanced reactive oxygen species production.

Supporting the primary importance of mitochondria in the aging process and in determining longevity, it has been documented that several mutagenic chemicals and lipophilic carcinogens eg, polycyclic aromatic hydrocarbons tend to preferentially damage mitochondrial DNA Wunderlich et al ; Allen and Coombs ; Niranjan et al ; Rossi et al It can then be hypothesized that a life-long exposure to these environmental toxins may lead to a preferential accumulation of mitochondrial DNA damage and accelerate aging. The superoxide anion radical or superoxide and hydrogen peroxide, respectively the products of the univalent and bivalent reduction of oxygen, are produced during normal aerobic metabolism and constitute physiological intracellular metabolites Cadenas and Davies Several reactions in biological systems contribute to the steady state concentrations of superoxide and hydrogen peroxyde, although mitochondria seem to be quantitatively the most important source Cadenas and Davies Although mild amounts of oxidative damage such as that experienced during exercise training Davies et al may actually be the stimulus for physiological mitochondrial biogenesis, more severe, more extensive, or more prolonged oxidative damage is clearly toxic Cadenas and Davies The gene regulation theory of aging proposes that senescence is the resulting of changes occurring in the gene expression Kanungo ; Weinert and Timiras Although it is clear that many genes show changes in expression with age, it is unlikely that selection could act on genes that promote senescence directly Weinert and Timiras To date, evidence in this field remains controversial, and aging should be more safely considered as a stochastic process, rather than a programmed mechanism directly governed by genes.

At least 15 different genetic manipulations inducing life extension in organisms such as yeast, fruit flies, nematodes, and mice have been demonstrated Butler et al However, it is still unknown how the proteins coded by these genes are acting in the regulation of longevity. On the other hand, other studies performed using animal models have suggested that genes supposed to be involved in aging are not able to reverse or arrest the inexorable expression of the molecular disorder that is the hallmark of aging Hayflick Because genes do not drive the aging process, an understanding of the human genome, even beyond what is known today, will not provide insights into a process that is random and thermodynamically driven Hayflick Recently, an insulin-like signaling pathway regulating life span in worms, flies, and mice has been identified Tatar et al Life span extension results from the activation of a conserved transcription factor in response to a reduction in insulin-like signaling, suggesting that gene expression can regulate life span.

Studies of human centenaries and their relatives have identified a significant genetic aspect of the ability to survive to exceptional ages. By identifying a locus on chromosome 4 that may contain gene s promoting longevity Puca et al , it has recently been supported the theory of a genetic component for exceptional longevity. If it will be confirmed that changes in gene expression can modulate the aging process, a major step forward the understanding of aging will be completed and a starting point for the development of interventions aimed at delaying aging provided. Gene manipulations possible in laboratory animals appear to have limited potential for direct application in humans, although they do provide insight into important biological factors in longevity determination in model systems.

In contrast, the potential of cell replacement therapy in reversing some of the adverse effects of aging appears to be substantial. Aging is accompanied by some loss of tissue function, which is at least partially due to either the age-related loss of cells from the tissue or an increased proportion of dysfunctional cells. The recent isolation of nearly totipotent cells, such as human embryonic stem cells, offers a great range of potential opportunities. These cells express telomerase and appear to maintain an immortal phenotype even after extended culture in vitro.

Cells and tissues derived from such cultures may provide the unique advantage of possessing a large replicative capacity and broad differentiation potential. However, it is important to note that formidable hurdles are yet to be overcome. Cells derived from established human embryonic stem cell lines will probably not prove to be immunologically compatible with most patients.

This may be resolved by immunosuppressive therapy, genetic modification of the cells to reduce immunogenicity, or possibly the creation of a chimeric immune system in the patient to induce tolerance. The ethics of the embryonic stem cell technology and the use of nuclear transfer in medicine is currently a matter of intense debate. Finally, it remains to be seen whether such new tissue even if it were autologous would be adequately vascularized and subsequently function appropriately in the patient. The cellular senescence theory of aging was formulated in when cell senescence was described as the process occurring in normal human cells in culture and characterized by a limited number of cell divisions Hayflick Telomeres are specialized DNA sequences located at the ends of eukariotic chromosomes.

Telomeres are synthesized by telomerase, a ribonucleoprotein reverse transcriptase enzyme that maintains the lengths of chromosomes Lingner et al Telomere sequences stabilize chromosomal ends by binding to proteins that prevent them from being recognized as double-stranded breaks by repair enzymes de Lange The attrition of chromosomal termini, caused by loss of telomerase, can lead to breaks and subsequent translocation, fusion, or rearrangement within these DNA regions de Lange The telomerase enzyme, which stabilize chromosomal termini by adding telomere repeats to the ends of chromosomes using a dedicated RNA template Greider and Blackburn ; Artandi , is of considerable interest to gerontologists.

Its expression is thought to be necessary for cellular immortalization Rhyu , and its absence may constitute a fundamental basis for cellular aging Harley et al ; Ahmed and Tollefsbol ; Artandi Immortal cells in general have a stable telomere length and mortal cells have telomeres that shorten with each cell division, thus establishing a link between the presence of telomerase, chromosomal stability, and the mortality of cells.

In fact, specialized immortal cell types such as stem cells, germ cells, and T lymphocytes express telomerase and will either maintain telomere length or delay telomere attrition. In actively dividing differentiated cells, with each cell division, a small amount of DNA is necessarily lost at each chromosome end, resulting in ever-shorter telomeres and altered telomere structure, eventually leading to the cessation of cellular proliferation Blackburn ; Weinert and Timiras This progressive shortening of telomeres starts soon after conception, when cells begin widespread differentiation.

Although in some of these cells telomerase is inactivated before birth, in others some telomerase activity can be detected after birth Ulaner and Giudice ; Ahmed and Tollefsbol Thus, telomere shortening and the loss of telomerase in normal somatic cells have been implicated as a potential molecular clock triggering cellular senescence Harley et al , loss of proliferative capacity, and age-related pathologies Campisi ; Fossel Cells that have been supplied with an exogenous source of telomerase maintain a youthful state and proliferate indefinitely Bodnar et al Thus, the biological and potential medical consequences of telomerase expression appear to be highly significant.

Supporting the hypothesized relationship between telomeres and aging, it has been demonstrated that some telomere dysfunctions are involved in the premature aging characteristic of progerias. Therefore, by extension, as it happens in the premature aging, telomeres might be, at least partially, responsible for the normal human aging Artandi The human telomerase reverse transcriptase hTERT , the active component of telomerase, has been identified and cloned and its messenger RNA is undetectable in differentiated cells that do not express telomerase, but is abundant in undifferentiated cells expressing telomerase Meyerson et al Although post-transcriptional mechanisms may modify hTERT activity Liu et al , the expression of hTERT correlates directly with telomerase activity and substantial evidence indicates that hTERT activity is controlled primarily at the level of transcription Cong et al ; Wick et al Unfortunately, little is still known about the switching mechanism that controls telomerase expression, leading to its down-regulation and subsequent cellular mortality in somatic cells.

Moreover, even if studies of telomere shortening and telomerase show great promise in helping to elucidate the underlying basis of cellular aging, it is not yet clear how this knowledge would enhance our understanding of aging of the individual. In fact, it is possible the presence of some tissues in which proliferative failure contributes to the declining physiology associated with aging, but those tissues have not been unequivocally identified. Moreover, many telomerase-negative immortalized cell lines can maintain their telomere lengths Bryan et al On the other hand, hybrids of telomerase-negative and telomerase-positive cells have failed to become immortal, so that it is likely that telomerase enzyme alone is insufficient to prevent cell senescence Bryan et al Although studies to this point indicate that telomerase may be intimately involved in cellular senescence and holds great promise, our understanding of these age-related mechanisms is still at the beginning.

The amount of currently available evidence for claiming that preventing telomere shortening would influence any aspect of aging is still insufficient. Even if the involvement of the inflammatory process in several sub clinical conditions eg, atherosclerosis, diabetes, dementia is well-demonstrated, the importance of inflammation in the aging process was recognized only recently McGeer and McGeer ; Chung et al Acute as well as chronic inflammatory responses are constituted by sequential phases, controlled by humoral and cellular stimula: 1 intracellular activation; 2 proinflammatory cells in the tissues; 3 increase of vascular permeability; 4 damaging of tissues and cell death Huerre and Gounon ; Chung et al An individual threshold of the capability to cope with stress has been hypothesized.

If the age-related inflammation or inflamm-aging trespasses this level, the transition between successful and unsuccesful aging occurs. Epidemiologic data support the hypothesis that the period of life during unsuccessful aging disability is maximal in the elderly, and minimal in young people and centenarians Franceschi et al a. Even when debating about inflammation and its relationship with aging, it is important to underline how this mechanism is associated with others at the basis of different theories of aging.

In fact, the close relationship between inflammation and oxidative damage is well-known in literature Cesari et al In fact, reactive oxygen species and reactive nitrogen species are heavily implicated in the inflammatory processes. The overproduction or uncontrolled release of reactive species is a major causative factor in tissue inflammation. In , Franceschi proposed the immune theory of aging, or network theory of aging Franceschi ; Franceschi et al a , in which suggested that aging is indirectly controlled by a network of cellular and molecular defense mechanisms.

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The major parts of the network are constituted by DNA repair enzymes, activation of poly ADP-ribosyl polymerase, enzymatic and nonenzymatic antioxidant systems eg, superoxide dismutase, catalase, glutathione peroxidase , production of heat shock proteins Franceschi ; Franceschi et al b. These mechanisms function to limit the negative effects of a variety of physical, chemical, and biological stressors.

The efficiency of the network is genetically controlled and differs among species and individuals, explaining in this way the observed differences in life span. In the network theory of aging, the immune system represents the most powerful mechanism to face stressors Franceschi et al a. In particular, Franceschi identified the macrophage as the primary modulator of the vicious cycle existing between innate immunity, inflammation and stress. The macrophage activation due to chronic stress may provide a potential explanation to the subclinical chronic inflammatory status characterizing older persons and, at the same time, a possible feature of the aging process.

Supporting this hypothesis and the importance of the immune system in determining the senescence is the evidence of the high incidence of tumors and greater susceptibility to infections from pathogens shown by the older persons. It has been suggested that aged subjects maintaining their immune functions at an exceptionally high level are more likely to have a long life span Wayne et al ; Pawelek et al As noted above, theories of aging often overlap each other, suggesting interactions across different systems and mechanisms.

In this context it should be considered the association between the immune cell functions such as those involved in the cytotoxic activity and particularly in phagocytes as regards their microbicidal activity and the reactive oxygen species generation. The excessive amount of reactive oxygen species not counteracted by the antioxidant defenses can become a potential source of tissue damage De La Fuente Moreover, antioxidants maintain the integrity and function of membrane lipids, cellular proteins, and nucleic acids and the control of signal transduction of gene expression in immune cells.

Not surprisingly, immune system cells usually contain higher concentrations of antioxidants than do other cells Knight , given the high percentage of polyunsatured fatty acids in their plasma membranes. It is generally accepted a bidirectional communication between the nervous and the immune systems Besedovsky and Del Rey With aging not only a functional decline in the immune and nervous systems occurs, but also an impaired relationship between these two regulatory systems can become evident, with the resulting loss of homeostasis and higher risk of death Fabris ; De La Fuente The neuroendocrine theory proposes that aging is due to changes in neural and endocrine functions that are crucial for:1 coordination and responsiveness of different systems to the external environment; 2 programming physiological responses to environmental stimuli; and 3 the maintenance of an optimal functional status for reproduction and survival.

These changes, not only selectively affect neurons and hormones regulating evolutionarily significant functions such as reproduction, growth, and development, but also influence the regulation of survival through adaptation to stress. Alterations of the biological clock eg, reduced responsiveness to the stimuli regulating the clock, excessive or insufficient coordination of responses would disrupt the clock and the corresponding adjustments Finkel ; Timiras ; Weinert and Timiras An important component of this theory indicates the hypothalamo-pituitary-adrenal HPA axis as the primary regulator, a sort of pacemaker signaling the onset and termination of each stage of life.

The HPA axis controls the physiological adjustments aimed at the preservation and maintenance of an internal homeostasis despite the continuing changes in the environment Weinert and Timiras Aging should then be considered as the result of a decrease ability to survive stress, suggesting once more the close relationship between stress and longevity. The integration of responses to environmental stimuli seems to be carried out by hypothalamus from information derived in various cerebral structures. In response to hypothalamic signals, the hypophysis produces and secrets several hormones acting in the regulation of many important functions of the body.

This regulation is controlled by the release of hormones eg, growth hormone, oxytocin, vasopressin or by the stimulation of peripheral endocrine glands eg, adrenal cortex, thyroid, gonads. Major hormones of the adrenal medulla are the catecolamines epinephrine and norepinephrine, functioning as neurotransmitters for the sympathetic division of the autonomic nervous system and rapidly responding to any external or internal stress through circulatory and metabolic adjustments Weinert and Timiras With aging, a reduction in sympathetic responsiveness is characterized by: 1 a lower number of catecholamine receptors in peripheral target tissues; 2 a decline of heat shock proteins that increase stress resistance; and 3 a decreased capability of catecholamines to induce heat shock proteins.

The hormones of the adrenal cortex are glucocorticoids responsible for the regulation of lipid, protein, and carbohydrate metabolism , mineralcorticoids regulating water and electrolytes , and sex hormones. Among the latter is dehydroepiandrosterone, which has shown to decrease with aging.

Dehydroepiandrosterone replacement therapy has been advocated in humans, despite unconvincing results Daynes and Araneo Glucocorticoids, as well as other steroid hormones, are regulated by positive and negative feedbacks between the target hormones and their central control by the hypophysis and hypothalamus. With aging and in response to chronic stress, not only feedback mechanisms may be altered, but also glucocorticoids themselves become toxic to neural cells, thus disrupting feedback control and hormonal cyclicity Sapolsky et al ; Sapolsky ; Weinert and Timiras The circulating levels of growth hormone, testosterone, estrogen, dehydroepiandrosterone, and other hormones decrease with age.

Although some hormone replacement strategies have been shown in clinical trials to modify some of physiological attributes associated with aging, negative side effects occur frequently with those interventions shown to have some benefit, such as growth hormone. Although the epidemiological data are overwhelmingly positive regarding some health benefits of estrogen replacement therapy, a recent study has raised a concern about ovarian cancer after long-term use. In order to adequately address hormone decline occurring with aging, it is crucial the understanding of the complex hormonal cascade, an intricate interplay between signals, pathways, and production and delivery systems.

Estrogen replacement therapy represents a special case of hormone replacement therapy and deserves particular attention because of its long clinical history and apparent record of success in increasing quality of life in postmenopausal women. Estrogen is particularly recommended for the prevention of osteoporosis, but it has been suggested it may reduce the risk of dementia and cardiovascular disease. The conclusion that estrogen protects postmenopausal women against cardiovascular disease is now being questioned, based mainly on experiments examining secondary prevention in women with preexisting heart disease.

Estrogen replacement therapy has been called the first true anti-aging therapy. However, no results have yet been reported of randomized studies that compare effects of this therapy with placebos, beginning at the menopausal transition, in women with no known preexisting coronary heart disease or dementia.

It has been demonstrated that circulating levels of growth hormone drop with increasing age. It has also been shown that GH replacement in adults with pituitary disease and GH deficiency has beneficial effects on body composition, reducing fat and increasing lean body mass, muscle strength, and bone mass. Rudman and colleagues investigated whether GH injections in older men would restore muscle mass typical of younger men.

They found that insulin growth factor IGF -1 levels did rise and that lean body mass increased while fat mass decreased, suggesting that GH injections did reverse the changes in body composition that were due to age and deconditioning. Recent data obtained with mice suggest that lifelong overproduction of GH reduces longevity in mice, whereas underproduction or an inability to respond to GH increases it.

Transgenic mice overexpressing GH exhibit severe kidney lesions and increased incidence of neoplasms, and overproduction of GH in adult humans leads to a condition known as acromegaly, which is characterized by excessive growth of certain organs and tissues, but also premature heart and lung failure. The evidence from both nematodes and fruit flies suggests that decreased activity of the insulin-like signaling pathway is associated with increased life expectancy, rather than the reverse. In the hierarchy of multisystem regulation throughout the sequential stages of life, there is a significant role for the interaction and integration of the neuroendocrine and immune systems.

Such interaction occurs through 1 neuropeptides and cytokines present in the immune system mediating both intraimmune communication and between the neuroendocrine and immune systems, 2 several hormones from the posterior vasopressin and anterior thyroid-stimulating hormone, prolactin, adrenocorticotropic hormone, growth hormone hypophysis, and 3 reciprocal action of cytokines on neuroendocrine functions. Besides of neuroendocrine interactions, the immune system must control and eliminate foreign organisms and substances in the host body while at the same time recognizing, and therefore sparing from destruction, the molecules from oneself.

In most older persons, immunosenescence is characterized by a decreased resistance to infectious diseases, a decreased protection against cancer, and an increased failure to recognize self leading to consequent autoimmune pathology Franceschi et al b. Both the neuroendocrine and immune systems are characterized by a high degree of plasticity and are able to modify their functioning according to demand.

Plasticity is most efficient at early ages, but persists at advanced age. Mechanisms of successful aging are based on: 1 persistence of normal function and plasticity, 2 compensatory responses to restore normal function, 3 interventions to replace deficient functions, 4 changing of health outcome by modifying risk profiles, 5 prevention of disease, and 6 strengthening of social interactions and support Rowe and Kahn A single chapter in this review is deserved by caloric restriction, the only nongenetic intervention that has consistently shown to slow the intrinsic rate of aging in mammals Dirks and Leeuwenburgh It is defined by the reduction in caloric intake while maintaining essential nutrient requirements.

How is caloric restriction able to increase lifespan? It is likely that this intervention can obtain beneficial effects by acting at various levels of function and involving a number of molecular cellular, and systemic changes. Not only is longevity increased, but also metabolic eg, increased tissue sensitivity to insulin , neuroendocrine and immune eg, increased defenses against stress, infections, cancer , and collagen responses eg, reduction of cross-linking are significantly enhanced Mobbs et al It is noteworthy that such functional changes might also be modulated by changes in gene expression profile.

Caloric restriction may promote longevity by a metabolic reprogramming with a transcriptional shift perhaps triggered by insulin toward 1 reduced energy metabolism, and 2 increased biosynthesis and turnover of proteins. It has also been demonstrated that caloric restriction markedly influences the expression of pathological phenotypes in rodent species selectively bred as models of human pathology Weinert and Timiras Even if the short-term effects in humans are promising Walford et al ; Weyer et al ; Fontana et al , long-term studies are not surprisingly difficult to conduct in humans.

The lack of data from human models is mainly due to the difficulties of adhering to this rigorous intervention and the length of the human life span. Biosphere 2 is a closed ecological space located in the deserts of Arizona. In , eight individuals entered the biosphere for a two-year period to study the effects from living in a closed system.

Physiological and biochemical measurements were assessed over the time spent inside the biosphere ie, while crew members experienced caloric restriction as well as 18 months after exiting the biosphere and returning to their normal diets. The physiological modifications experienced by the Biosphere 2 participants were similar to those found in caloric restricted rodents and nonhuman primates: decline in metabolic rate, body temperature, and systolic and diastolic blood pressure, and reductions in blood glucose, insulin, and thyroid hormone levels.

It has been shown that the Okinawan population is characterized by reduced morbidity and mortality, and the greatest percentage of centenarians in the world lives in this island. It is noteworthy that this diet is very similar to the caloric restriction interventions designed for experiments in animal models.

Despite of the abundant data showing health benefits and the reduction of the aging rate by use of a caloric restriction intervention in mammalian animal models, it is likely that these beneficial effects will be lost in the translation to human models Dirks and Leeuwenburgh Nevertheless, the elimination of this clinical condition will have only a minimal impact on life expectancy and will not help the advancing of our knowledge of fundamental biology of aging.

Greater attention has to be given to a rarely posed question: why are old cells more vulnerable to disease than young cells? The answer to this issue will not only advance our fundamental knowledge of aging, but also promote the understanding of age-related diseases Hayflick a. Several and important step forward the understanding of the aging process have been done, so that it is no more an obscure issue of biology Holliday Nevertheless, further studies are still needed and numerous cues solved.

In particular, it is important to clarify to which extent and at which price the aging process can be limited or reversed. National Center for Biotechnology Information , U. Journal List Clin Interv Aging v. Clin Interv Aging. Author information Copyright and License information Disclaimer. All rights reserved. This article has been cited by other articles in PMC. Abstract Aging is commonly defined as the accumulation of diverse deleterious changes occurring in cells and tissues with advancing age that are responsible for the increased risk of disease and death.

Keywords: Aging, anti-aging medicine, caloric restriction, oxidative damage, inflammation, physical exercise. Introduction Aging is commonly defined as the accumulation of diverse deleterious changes occurring in cells and tissues with advancing age that are responsible for the increased risk of disease and death Harman Evolutionary theory of aging Evolutionary theory indicates aging as the result from a decline in the force of natural selection.

CMV has been rigorously investigated for its impact on lifelong immunity and potential complications arising from lifelong infection. A rigorous adaptive immune response mounts during progression of CMV infection from acute to latent states. CD8 T cells , in large part, drive this response and have very clearly been demonstrated to take up residence in the salivary gland and lungs of infected mice during latency.

However, the role of tissue resident CD8 T cells as an ongoing defense mechanism against CMV has not been studied in other anatomical locations. Therefore, we sought to identify additional locations of anti-CMV T cell residency and the physiological consequences of such a response. We further found, through flow cytometry , that adipose tissue became enriched in cytotoxic CD8 T cells that are specific for mCMV antigens from day 7 post infection through the lifespan of an infected animal and that carry markers of tissue residence.

Furthermore, we found that inflammatory cytokines are elevated alongside the expansion of CD8 T cells. Finally, we show a correlation between the inflammatory state of adipose tissue in response to mCMV infection and the development of hyperglycemia in mice. Overall, this study identifies adipose tissue as a location of viral infection leading to a sustained and lifelong adaptive immune response mediated by CD8 T cells that correlates with hyperglycemia. This data potentially provides a mechanistic link between metabolic syndrome and chronic infection.

That microRNA mir beneficially affects heart regeneration was discovered via its presence in embryonic stem cell exosomes. Exosomes are extracellular vesicles , membrane-bound packages of molecules that cells pass between one another. They are interesting to the research community because it is in principle much easier to construct a therapy based on delivery of exosomes harvested from stem cells than it is to deliver those same stem cells.

Thus most of the present generation of stem cell therapies may well be replaced in the near future by the delivery of extracellular vesicles, and many research groups are testing exosomes from stem cells to see how well they work to spur greater regeneration. Most vesicles contain a wide variety of molecules, but in the case of embryonic stem cell exosomes and the injured heart, researchers found that near all of the therapeutic effect was mediated by mir Thus they could go a step further and discard the exosomes as well as the cells.

The results of that line of work are noted in today's publicity materials and paper. Applying mir causes adult heart muscle cells to regress into a state more like that of embryonic cells, provoking greater replication and thus greater regeneration. This sort of in-situ reprogramming of cell behavior is growing in popularity in the research community, see the work of Turn. By adulthood, the heart is no longer able to replenish injured or diseased cells. As a result, heart disease or an event like a heart attack can be disastrous, leading to massive cell death and permanent declines in function.

A new study is the first to show that a very small RNA molecule known as miR, when introduced into heart cells, can reactivate heart cell proliferation and improve heart function in mice that have suffered the equivalent of a heart attack in humans. But shortly after birth miR is no longer expressed. The heart is very proliferative when miR is expressed in early life. We wanted to see if reintroducing it into adult heart cells would turn them back to an embryonic-like state, allowing them to make new heart cells. The researchers tested their idea in mice that had myocardial infarction heart attack.

Mice were treated with miR continuously for two weeks after sustaining myocardial injury. Two months following treatment, the researchers observed noticeable improvements in heart function and a decrease in the area of damaged tissue. Examination of treated heart cells revealed evidence of cell cycle reentry, indicating that the cells had been reactivated, regaining the ability to produce new cells. Because of this, the old heart cells were no longer quite like adult cells, but neither were they fully embryonic. In this in-between state, however, they had the ability to make new cells.

Embryonic heart is characterized of rapidly dividing cardiomyocytes required to build a working myocardium. Cardiomyocytes retain some proliferative capacity in the neonates but lose it in adulthood. Consequently, a number of signaling hubs including microRNAs are altered during cardiac development that adversely impacts regenerative potential of cardiac tissue. Embryonic stem cell cycle miRs are a class of microRNAs exclusively expressed during developmental stages; however, their effect on cardiomyocyte proliferation and heart function in adult myocardium has not been studied previously.

In this study, we determine whether transient reintroduction of embryonic stem cell cycle miR promotes cardiomyocyte cell cycle reentry enhancing cardiac repair after myocardial injury. A doxycycline -inducible AAV9 -miR vector was delivered to mice for activating miR in myocytes for 14 days continuously after myocardial infarction.

The aging process and potential interventions to extend life expectancy

Myocyte cell cycle reentry increased in miR hearts parallel to increased small myocyte number in the heart. Isolated adult myocytes from miR hearts showed upregulation of cell cycle markers and miR targets 8 weeks after MI. Thus ectopic transient expression of miR recapitulates developmental signaling and phenotype in cardiomyocytes promoting cell cycle reentry that leads to augmented cardiac function in mice after myocardial infarction. The brain is an energy-hungry organ, and the supply of oxygen and nutrients to brain tissue is vital to its function.

This is one of the reasons why cardiovascular disease contributes to neurodegeneration. Researchers know that cells that wrap small blood vessels in the brain, called pericytes , tend to become dysfunctional or die in later life , another of the cellular casualties of the damage of aging. This causes greater constriction of the blood vessels, reducing the blood flow to tissues. This is an intriguing addition to what is known of the issues caused by protein aggregation in neurodegenerative conditions.

A new study looked at the role of pericytes, cells wrapped around capillaries that have the ability to contract and regulate blood flow. Researchers examined capillaries in Alzheimer's-affected human brain tissue and in mice bred to develop Alzheimer's pathology, and found that they were squeezed by pericytes.

They also applied amyloid beta protein which accumulates in the brains of people with Alzheimer's to slices of healthy brain tissue, and found that the capillaries were squeezed as a result. They calculated that the constriction was severe enough to halve blood flow, which is comparable to the decrease in blood flow found in parts of the brain affected by Alzheimer's.

Since reduced blood flow is the first clinically detectable sign of Alzheimer's, our research generates new leads for possible treatments in the early phase of the disease.

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Damage to synapses and neurons in Alzheimer's is usually attributed to the actions of amyloid and tau proteins accumulating in the brain. Our research raises the question of what fraction of the damage is a consequence of the decrease in energy supply that amyloid produces by constricting the brain's finer blood vessels.

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In clinical trials, drugs that clear amyloid beta from the brain have not succeeded in slowing mental decline at a relatively late phase of the disease. We now have a new avenue for therapies intervening at an earlier stage. The heart regenerates only very poorly, and responds to injury by producing scar tissue, a process that involves fibroblast cells. Additionally, the age-related disruption of regenerative processes produced by senescent cells and chronic inflammation tends to empower fibroblasts to produce fibrosis in the heart even in the absence of injury.

One potential approach to the challenge of poor heart regeneration and growing fibrosis is to reprogram the fibroblasts of scar tissue into functional heart muscle cells, cardiomyocytes. Given recent demonstrations of in situ cell reprogramming, it is plausible to think that this can be accomplished. The challenge is to do so without disrupting the vital structural and electrical properties of heart tissue.

A heart attack leaves damaged scar tissue on the heart and limits its ability to beat efficiently. But what if scientists could reprogram scar tissue cells called fibroblasts into healthy heart muscle cells called cardiomyocytes? Researchers have made great strides on this front with lab experiments and research in mice, but human cardiac reprogramming has remained a great challenge.

Now, for the first time, researchers have developed a stable, reproducible, minimalistic platform to reprogram human fibroblast cells into cardiomyocytes. The researchers introduced a cocktail of three genes - Mef2c , Gata4 , and Tbx5 - to human cardiac fibroblast cells with a specific optimized dose.

Chapter 13. Aging and the Elderly

To increase efficiency, they performed a screen of supplementary factors and identified MIR , a small RNA molecule that when added to the three-gene cocktail - and with further in- culture modifications - reprogrammed human cardiac fibroblast cells into cardiomyocytes at an efficiency rate of 40 to 60 percent. Analysis identified a critical point during the reprogramming process when a cell has to "decide" between progressing into a cardiomyocyte or regressing to their previous fibroblast cell fate. Once that process begins, a suite of signaling molecules and proteins launch the cells onto different molecular routes that dictate their cell type development.

The researchers also created a unique cell fate index to quantitatively assess the progress of reprogramming. Using this index, they determined that human cardiac reprogramming progresses at a much slower pace than that of the previously well-described mouse reprogramming, revealing key differences across species and reprogramming conditions. Those portions of the modern longevity community interested in bringing an end to aging and extending healthy human life span indefinitely tend to be the older portions, people who have been a part of the broader movement for quite some time.

Newcomers tend to be more moderate, aiming at lesser goals. Perhaps this is a result of the successful projects, such as the SENS Research Foundation and Methuselah Foundation , tending to moderate their rhetoric as they attract a broader and larger base of support. I think that this road to moderation might be a problem, and that there is thus a continued role for those who loudly declaim that the goal is to control aging absolutely, via new medical technology, and that the natural consequence of that control is healthy, active, youthful life that extends for centuries or more.

If the goals that our movement works towards are broadly watered down from radical life extension of centuries to just adding a few more years, then marginal projects that can do no more than add a few more years will come to dominate the field to the exclusion of everything else. We are already more or less in this situation, in that that the vast majority of funding goes towards discovery and development of small molecules that tinker with the operation of an aged metabolism to make it a little more resilient to the underlying causes of aging.

If that is all that is done, then we'll all age and die on basically the same schedule as our parents and grandparents. It will be a grand waste of opportunity, given that we have the knowledge and the means to do far better, such as by following the SENS agenda for rejuvenation biotechnologies based on repairing the root causes of aging. This popular media article looks at a few of the people who do make no bones about aiming at radical life extension.

It isn't terrible, thankfully, though it doesn't quite manage to escape the straitjacket of conformity, the author suggesting that it is somehow strange to want to live for a long time in good health, or strange to want to avoid a slow, crumbling, painful death. There is no present status quo so terrible that it will not have its defenders, and for whatever reason the status quo of aging and suffering and omnipresent death and loss are aggressively defended. But setting that aside, the article manages to capture the present state of development and the viewpoints of its subjects quite well, which is a change over past years of media attention.

How to live forever: meet the extreme life-extensionists. In , an American real-estate investor named James Strole established the Coalition for Radical Life Extension , a nonprofit based in Arizona which aims to galvanise mainstream support for science that might one day significantly prolong human life. Standards in modern medicine are allowing us to live longer now than ever before.

But that is not Strole's concern. What good are a few more measly years? He is interested in extending life not by days and weeks, but by decades and even centuries, to the degree that mortality becomes optional - an end to The End. He isn't alone. Life extensionists have become a fervent and increasingly vocal bunch. Famously, the community includes venture capitalists and Silicon Valley billionaires, non-gerontologists all, and nearly all men, who consider death undesirable.

The current life-extensionist strategy is twofold. First, achieve a "wellness foundation," Strole says. Second, stay alive until the coming gerontological breakthrough. All that is required is to " live long enough for the next innovation ," and presuming you do, "You can buy another 20 years. This is a common view. Last year the British billionaire Jim Mellon , who has written a book on longevity, titled Juvenescence , said: "If you can stay alive for another 10 to 20 years, if you aren't yet over 75 and if you remain in reasonable health for your age, you have an excellent chance of living to more than Why not forever?

He invokes the analogy of a ladder: "step by step by step" to unlimited life. In the American futurist Ray Kurzweil coined a similar metaphor, referring instead to " bridges to immortality ". Aubrey de Grey , a serious scientist, considers life extension a health issue, which is perhaps the field's most convincing argument.

Gerontologists are not hoping to end death, he says. Instead, "We're interested in people not getting sick when they get old. Gerontology is the act of developing treatments for age-related diseases, de Grey argues - of reducing the causes of death, not death itself. The benefits are not having Alzheimer's disease. Are we anywhere near to a breakthrough? So far, research has produced modest yields. Gerontologists speak prophetically of potential, but most warn a significant human development remains somewhere far off in the distance - almost in sight but not quite.

Richard Hodes , the director of the National Institute of Aging , a US government agency, told me that, though research in animals has led to "dramatic increases in lifespan", some of them multi-fold, "There has been far less quantitative effect as those models have moved towards mammalian species.

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Much of gerontology focuses on identifying types of damage that accumulate with age and developing ways to halt or reverse that accumulation. It has been discovered, for example, that as we grow older, certain cells become senescent and harmful but nevertheless stick around, getting in the way like comatose guests at the end of a house party.

Removing those cells have helped mice have longer, healthier lifespans. Similar forms of genetic engineering have been successful in other animal models. But to reach the mainstream, gerontologists must convince government agencies to support human adoption, a complicated and long-winded task, given the general view that death is a normal human process. The authors of this open access paper review the aging of the kidney and consider the prospects for using factors from young blood as a means of rejuvenation.

This is a fairly narrow view, as there are many other approaches that should produce rejuvenation of the aged kidney, ranging from those close to realization, such as senolytic therapies to clear senescent cells, or various approaches to stem cell therapy, to those yet to be achieved, meaning much of the rest of the SENS agenda of rejuvenation biotechnologies to repair the damage that causes aging. Nonetheless, after so many years of trying to persuade the research community to open up on the topic of addressing the mechanisms of aging as a means of therapy, it is very pleasant to see so many publications in the literature doing just that.

The present open discourse is a sea change in comparison to the silence of a decade or two ago , in which few researchers were willing to speak in public about treating aging. The science was always valid and promising, it is the culture that has changed for the better. It is well established that aging is associated with structural and functional renal changes. With the possible exception of the lung, the changes in kidney function with normal aging are the most dramatic of any human organ or organ system.

Functionally, the aging kidney has a parallel decline in both glomerular and tubular function. The Baltimore longitudinal study demonstrated an average of 0. The GFR loss rate is tripled in subjects over 40 as compared with those under Cellular senescence describes an everlasting growth arrest of still viable and metabolically active cells. The cell-cycle regulators and tumor suppressors p16Ink4a and p19ARF are involved in cellular senescence. The expression of p16 Ink4a in the kidney has been known to increase with age and could be found in a variety of renal cell types.

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Renal p16Ink4a expression has been suggested as an ideal marker for renal aging and shown to foresee transplant outcome. In normal human glomerular, p16Ink4a expression is increased with age and in all resident cell types. Studies in a transgenic mouse model confirmed that ablating p16Ink4a positive senescent cells not only prolongs the lifespan, but also attenuates glomerulosclerosis in aging kidney and decreasse blood urea nitrogen levels. Furthermore, depletion of p16Ink4a resulted in reduction of renal interstitial fibrosis and nephron atrophy in mice after ischemia-reperfusion injury , indicating inhibition of senescence provides a protective effect on the development of fibrosis.

Considering the increase of the aging population, it is extremely urgent to identify a way to retard the aging process or rejuvenate the community. To test the effects of young blood on aged organ, young blood infusion or parabiosis may be used. Parabiosis is an experimental model aiming to join the circulatory system of two animals. Heterochronic parabiosis is used to connect an aged partner to a young partner, and can be used to demonstrate the effects of young blood on aged organs, and vice versa.

With this model, rejuvenation in the aged heterochronic parabiont has been shown in different organs such as muscle, liver, brain, and heart. Moreover, recent studies provided evidence that young systemic milieu may alleviate renal ischemia-reperfusion injury in elderly mice probably through reduction of oxidative stress , inflammation , apoptosis , and enhancement of autophagy in the injured aged kidney.

Although evidence showed that young blood can attenuate renal aging and injury induced by ischemia-reperfusion injury in elderly mice, it will be important to identify and study the effects of specific blood-borne rejuvenating factors in the young blood or aging factors in the old blood in addition to put efforts into delineate the mechanisms underlying the renal cell senescence. This information will provide novel ideas to turn back the clock of the aging kidneys.

It is well known that the most commonly available forms of stem cell therapy produce benefits via signaling on the part of the transplanted cells, which soon die, rather than via any sort of integration of these cells into tissues. These treatments use varieties of what are called mesenchymal stem cells , which is actually a poorly defined, broad category.

One clinic's mesenchymal stem cells are usually meaningfully different from those of the next. Nonetheless, these therapies fairly reliably reduce chronic inflammation. This can allow for improved regeneration in patients, but that outcome is much less reliable in practice. The innate immune cells known as macrophages are important in the complex dance of tissue regeneration.

In recent years researchers have become increasingly interested in deciphering and altering macrophage behavior, switching more of these cells from the aggressive and inflammatory M1 polarization , responsible for hunting pathogens , to the pro-regenerative M2 polarization. It is thought that aging is characterized by too much of a bias towards M1, and the balance might be forced back to M2 via the application of suitable therapies. It is perhaps not surprising that we should find that some existing therapies that can modulate inflammation and improve regeneration act through this mechanism.

More and more studies have shown that stem cells can play an important role in tissue repair and anti-inflammation. In particular, mesenchymal stem cells MSCs have shown anti-inflammatory and immunological functions. Indeed, MSCs have also been shown to have the potential to enhance the recovery and regeneration of the infarcted myocardium. The current belief on the role of MSCs in myocardial regeneration is their synthesis and secretion of cytokines and other trophic growth factors to signal to the injured myocardial cells, which may also involve anti-aging effects.

Many effects of MSCs on tissue repair and cell regeneration are conducted through their crosstalk with macrophages. It is traditionally thought that macrophage are deemed to be white blood cells with a major functionality of swallowing and ingesting wastes, dying or dead cells, and impurities.

Nevertheless, recently studies have shown that macrophages have much more functions other than phagocytosis. Therefore, a more complicated classification of macrophages has been applied, in which 2 subtypes of macrophages are distinguished by two phenotypes.

One was named as "M1" macrophages, while the other alternatively polarized one was named as "M2" macrophages, which function in regulation of humoral immunity and promotion of tissue repair. Since the role of macrophages in the MSC-mediated recovery of heart function after MI remains unclear, this question was thus addressed in the current study.

We found that transplantation of MSCs did not alter the total number of the macrophages in the injured heart, but induced their polarization towards a M2-phenotype. Thus, our data suggest that MSCs may rejuvenate CMCs after ischemic injury at least partially through induction of M2-polarization of macrophages. A slow accumulation of long-lived senescent cells takes place throughout the body over the years, and is involved in the age-related decline of all tissues.

Cells become senescent constantly, in response to damage, a toxic environment, participation in the wound healing response , or simply reaching the Hayflick limit on replication. Near all newly senescent cells either quickly self-destruct or are soon hunted down by the immune system , but a tiny fraction survive to linger. Senescent cells do not replicate, but are very active, secreting a potent mix of inflammatory and other signals that disrupt cell behavior and tissue structure. A sizable fraction of the chronic inflammation of aging is produced by the activities of senescent cells, and this inflammation drives the progression of all of the common age-related diseases.

Why we age: Insight into the cause of growing old Why we age: Insight into the cause of growing old
Why we age: Insight into the cause of growing old Why we age: Insight into the cause of growing old
Why we age: Insight into the cause of growing old Why we age: Insight into the cause of growing old
Why we age: Insight into the cause of growing old Why we age: Insight into the cause of growing old
Why we age: Insight into the cause of growing old Why we age: Insight into the cause of growing old
Why we age: Insight into the cause of growing old Why we age: Insight into the cause of growing old
Why we age: Insight into the cause of growing old Why we age: Insight into the cause of growing old
Why we age: Insight into the cause of growing old Why we age: Insight into the cause of growing old

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