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.
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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.
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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.
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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. 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.
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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.
Certain vitamins and supplements can help you live your best life, and that mix can vary according to your stage of life, Dr. Consistency is the key. Vitamin D deficiency has been linked to a host of age-related diseases , many of which can shorten your life. Taking aspirin every day can reduce your risk of stroke or heart attack, but discuss with your doctor whether this therapy makes sense for you it can also increase the risk of uncontrolled bleeds.
Here are 15 habits that could be aging your brain. These is a class of drugs, known as senolytics, that might be able to improve our life spans, Dr. The drugs can also treat some forms of leukemia. Stay tuned. Rapamycin, a drug derived from a bacterium found on Easter Island in the southeastern Pacific Ocean, increases the life spans of mice. Jumping 40 times a day on a hard surface will strengthen your bones and spinal discs and decrease your risk of breaking a bone, Dr.enter
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Here are other ways to slash your risk of developing the brittle bone disease osteoporosis as you age. Make sure you are up-to-date on all of your shots and immunizations since this is the best way to keep your immune system in tip-top shape. Immunizations are especially important if you are one of the millions of people living with diabetes.
Sitting or being sedentary for long periods of time increases the risk for all sorts of diseases and conditions that can shorten lives, Dr. Smoking tobacco is linked to a laundry list of diseases that will shorten your life, including cancer, heart disease, and stroke. Your body will heal in lots of mind-blowing ways once you quit smoking.
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Telomeres are protective caps on the ends of our chromosomes that dictate how long cells live. Here are 30 anti-aging secrets that could add years to your life. Are you constantly getting left behind when walking with friends your age? Thankfully, this one has an easy fix: Take more walks and improve your fitness level. Sun damage is perhaps the most important cause of an older-looking face, as too much sun causes lines, wrinkles, dull skin, and the dreaded brown age spots to develop, says Joshua D. Start wearing sunscreen immediately and talk to a dermatologist about other options.
These are the best anti-aging products at every price point. Staying active by moving more and sitting less can help, she adds. For women, the frequency and predictability of your menstrual cycle can be an early sign of aging, and it can start 15 years before menopause. Gandhi says. Every product is independently selected by our editors. If you buy something through our links, we may earn an affiliate commission.
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