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Aging Processes of the Physical Body
By-product of cellular use of oxygen, or absorbed through environmental exposure=Free radicals: molecules that have lost an electron. When this happens to oxygen, we call it singlet oxygen because it has only one of its electrons left. This is a highly unstable condition. To restore balance, the radical tries to steal an electron away from (or donate the remaining one to) another nearby molecule. In so doing, the free radicals create "molecular mayhem," disrupting, damaging and destroying nearby cells.
As we age, some hormones begin a precipitous decline that strongly parallels the onset of aging signs and symptoms. These include human growth hormone, melatonin, DHEA, pregnenolone, androstenedione (made famous by Mark McGwire), testosterone, estrogen and progesterone. Conversely, insulin levels tend to rise, culminating in adult onset diabetes. A relative rise in cortisol, the stress hormone, is all too common. Although thyroid hormone doesn't generally fall with age, many anti-aging doctors insist that slow thyroid function is common and, when present, definitely hastens aging and heart disease. Human growth hormone (aka HGH), as the name implies, stimulates the growth of our tissues. Our internal organs, skin, muscles, nerves and bones are all stimulated to grow by HGH..
Latest Research on Changes in Circulating Hormones (HgH and IGF-1) as biomarkers of aging
Many of the body's functions are regulated by hormones. Hormones are released into the bloodstream from glands or organs. Hormones bind to the surface of cells and exert an effect on the cell's function. Most hormones decline with advancing age. In particular, levels of growth hormone and insulin-like growth factor (IGF-1) in the blood decline substantially with age. IGF-1 is released by the pituitary gland into the bloodstream. The hormone binds to cells all over the body, including the brain, exerting a growth effect. A decline in this hormone is thought to result in a reduction of activity of cells. William Sonntag and his colleagues at Wake Forest University School of Medicine are investigating the role of growth hormone and IGF-1 in aging and their possible use as biomarkers of aging. They've shown that the levels of these hormones decrease with age and, in an animal model, when IGF-1 is injected back into animals that are deficient in the hormone, age-related changes are reversed. This suggests that a diminishment of these hormones contributes to the aging process. The age-related effects of growth hormone and IGF-1 on bone and muscle mass have been studied extensively. Dr. Sonntag is looking at the effects of reduced IGF-1 in the brain. One brain region that suffers the most from aging is the hippocampus. This area, which plays a major role in memory and other cognitive functions, tends to shrink with age, and fewer new brain cells are formed. In a study by Dr. Sonntag and colleagues on rats, they found that IGF-1 appeared to regulate the formation of new brain cells in the hippocampus. Theoretically, therefore, a decline in IGF-1 with age could be partly responsible for memory difficulties and other cognitive difficulties some people experience in older age. If these findings are shown to be true for humans as well as rodents, levels of growth hormone and IGF-1 could be a biomarker of aging.
Telomeres are bits of DNA on the ends of our chromosomes -- think of the hard ends of your shoelaces. While they do not contain genes, telomeres are important for replication or duplication of the chromosomes during cell division. Each time a normal cell divides, its telomeres are cut just a bit shorter, until eventually they are so short that no further cell division can occur. Cells with critically short telomeres become senescent, unable to divide further, and eventually malfunction and die. While some have likened this to a genetic biological clock, others have described telomeres as a fuse that becomes shorter and shorter, until it sets off a kind of cellular time bomb that wreaks havoc on the cell's internal workings.
Inside the nucleus of virtually all of our cells are chromosomes, 46 in all. At the tips of these chromosomes are telomeres, repeating sequences of genetic material that shorten each time a cell divides. Cell division is important because many cells in our body (e.g., those that line our digestive tract) must be replaced over time. When a cell's telomeres reach a critically short length, however, that cell can no longer replicate. Its structure and function begins to fail, and ultimately, the cell dies. Some have likened the process of telomere shortening to a genetic biological clock that winds down over time.
DNA Damage and Repair [ Go to Page Top ]
In each moment, DNA, the genetic material in our cells, is damaged by internal and external toxins. Luckily, our bodies have developed intricate repair systems that maintain the integrity of this code and of our cells and their function. Over time, however, our DNA repair systems falter. Some scientists believe that the accumulation of uncorrected DNA damage over years is a major cause of aging.
Some scientists believe that the accumulation of uncorrected DNA damage over years is a major cause of aging. They cite the following observations:
Animals with the fastest rates of DNA repair generally have the longest life spans.
Animals with the highest rates of oxidative damage by free radicals (and specifically, with oxidative damage to DNA) generally have the shortest life spans.
In lower life forms subject to oxidative damage, anti-oxidant supplements, which can correct and prevent DNA damage when it occurs naturally, do increase life span. This has been shown in worms, insects and rats.
Exposure to external causes of DNA damage (ultraviolet light, tobacco) decreases life span.
Humans who have genetic diseases resulting in greater spontaneous DNA damage or inefficient DNA repair often show signs of premature aging.(8)
Evidence exists for the decline in DNA repair and the accumulation of DNA damage in several different types of cells taken from elderly subjects. Elderly patients' blood(9) and skin cells(10) have less capacity to repair themselves than those from young adults. Indeed, one study that looked in white blood cells found DNA damage in 2-4% of the cells from young adults, but six times more often in cells from the elderly.(11) These aging white blood cells with their higher level of DNA damage may explain some of the decline in immune function associated with aging.
DNA Damage [ Go to Page Top ]
Spontaneous and inherited gene mutations
The building blocks of genes are the nucleotides (chemically speaking, these are bases plus a sugar-phosphate that serves to link the bases). They are arranged in specific orders in each gene. If, in the course of cell reproduction, one nucleotide is substituted for another, a nucleotide is accidentally deleted, or an extra nucleotide is added, this is called a spontaneous mutation. If that mutation occurs in a germ (egg or sperm) cell, that mutation can be inherited by the next generation.Natural cell processes
The creation of energy in a cell utilizes oxygen. In addition to energy, that process produces toxic byproducts called reactive oxygen species. These are a class of free radicals, which can damage DNA as well as cellular proteins and fats.External causes
Ultraviolet light has been recognized as a cause of DNA damage for nearly 25 years.(4) X-rays can break the strands of DNA in cell nuclei. Toxins like benzo[a]pyrene(5), medications like those used in chemotherapy(6), and that most deadly poison, cigarette smoke, all cause DNA damage.
DNA Repair [ Go to Page Top ]
In both dividing and non-dividing cells, DNA is vital to their everyday functioning. The code in DNA is read by special enzymes and "translated" into the proteins that carry out all of our cellular and other bodily processes. Even small DNA errors can have serious effects. A single unrecognized and uncorrected DNA error can disable a critically needed protein and over time, result in disease or even death. DNA repair processes act by finding DNA damage and correcting it before too much of the damage is reproduced and accumulates. Some researchers contend that without DNA repair processes our cells would sustain enough damage to become useless within one year.
The genes in the nuclei of our cells are not the only sources of DNA in our cells. Cells also contain many tiny organelles called mitochondria. Mitochondria act as powerhouses for our cells, transforming oxygen and other fuels into the energy we need to live. Mitochondria possess their own DNA, and they use it to produce the proteins that carry out energy production. Because mitochondria use oxygen in energy production, their DNA is surrounded by free radicals (the toxic byproducts of energy production), and this greatly increases the amount of damage their DNA can sustain. For many years, scientists believed that mitochondrial DNA had no effective repair mechanisms. More recent research has shown that some mitochondrial DNA repair systems do in fact exist, but they are much less effective than those in the nuclei.(7)
Mitochondrial Aging [ Go to Page Top ]
Mitochondria are the cells' energy converters. We need them to transform nutrients into the energy we need to live. Mitochondria also produce damaging oxidants--free radical molecules produced by the metabolism of oxygen--that can wreak havoc on cells and their DNA. As the source of these toxic products, mitochondria are also their first potential victims. Their proximity to the free radicals they produce, combined with their exceedingly intricate structure, make them particularly vulnerable to injury over time. Not surprisingly, researchers are seeking to understand this injury as a critical part of the aging process, and perhaps a cause of a host of age-related diseases.
Aging Factors:
Oxidative Damage
Among the byproducts of mitochondrial energy production are "reactive oxygen species" that include hydrogen peroxide-the same hydrogen peroxide used as an antiseptic and hair bleach. (In fact, the bleaching action of hydrogen peroxide is visible evidence of its oxidative power.) Many of these reactive oxygen species are free radicals. The free radicals include superoxide and the deadly hydroxyl radical (the same type of free radical that is produced in nuclear explosions). Oxygen free radicals, unless they are quickly neutralized by antioxidants, can cause considerable damage to the membranes of mitochondria and to mitochondrial DNA. The injury caused by these free radicals initiates a self-perpetuating cycle in which oxidative damage impairs mitochondrial function, which results in the generation of even greater amounts of oxygen free radicals.
Over time, the affected mitochondria become so inefficient, they are unable to generate sufficient energy to meet cellular demands. Mitochondria from the cells of older individuals tend to be less efficient than those from (younger) the cells of younger people.
In a review published in the summer 2001 issue of Biological Signals and Receptors, Humboldt (Berlin) University Professor A. Kowald noted that the mitochondrial theory of aging, the theory that damaged mitochondria increase with age and are responsible for the physical changes of aging, is gaining in acceptance. In support of the theory, he remarked that mitochondrial diseases and mitochondrial DNA damage are more prevalent in aging organisms. Taiwanese researchers echoed Dr. Kowald, commenting that the damage to mitochondrial DNA is seen most prominently in tissues with high energy needs.
Mitochondria appear, then, to be an obvious focus of study for researchers who study aging. Their role as energy producers makes them absolutely crucial to the life of the cell. But they also produce threateningly large quantities of oxygen free radicals. As the source of these toxic products, mitochondria are also their first potential victims. Their proximity to the free radicals they produce, combined with their exceedingly intricate structure, makes them particularly vulnerable to oxidative injury over time.
Mitochondrial DNA is not as well protected as nuclear DNA
Mitochondrial DNA is not as well protected as nuclear DNA, which is coated by proteins. The "naked" mitochondrial DNA becomes an easy target for rogue reactive oxygen species. In a recently published study in Circulation Research, Scott Ballinger and colleagues at the University of Texas Medical Branch in Galveston found that when cultured animal cells were exposed to various types of oxygen free radicals, their mitochondrial DNA was more severely damaged than their nuclear DNA. Another study found that mitochondrial DNA damage was more extensive and persisted longer than nuclear DNA damage in human cells following oxidative stress. In general as cells age, the number of gaps and errors in their mitochondrial DNA tends to increase, and oxidant exposure is the likely cause. Controlling oxidative damage, therefore, appears to be one strategy for defeating some of the effects of aging.
Mitochondrial factors: Cardiolipin, CoQ and Carnitine
As the body ages, we absorb nutrients less efficiently, and this can affect the efficiency of mitochondrial function. Cardiolipin is a component of the energy-producing process that is found almost exclusively in mitochondria. Cardiolipin levels naturally decline with age. Lipid peroxidation, a type of oxidant damage more common in older cells, leads to a decrease in cardiolipin. Cardiolipin itself can suffer the effects of lipid peroxidation, and the progressive accumulation of crippled cardiolipin molecules is yet another way in which oxidant damage can jeopardize the efficiency of energy production.
Carnitine, an amino acid, is also important to mitochondrial metabolism because it helps chaperone fatty acids into the mitochondria, where they can be metabolized. Carnitine deficiency leads to an inability to harvest the energy stored in fatty acids and to a build-up of fatty intermediates that can prove toxic to cells. Again mitochondria from older cells tend to contain less carnitine. Carnitine and cardiolipin form complexes in the membranes of mitochondria, protecting them. Certain medications, including the cancer drug adriamycin, target carnitine as part of their action, and administration of the drug L-carnitine can reverse some of the damaging effects of those drugs, while permitting them to do their necessary work in the body.
Coenzyme Q10, also known as CoQ10 or ubiquinone, is another factor necessary for energy production. It is available in the diet and it can be manufactured from simpler precursors. CoQ10 deficiency can affect brain and nerve function, and aging skeletal muscle cell mitochondria contain less of this important factor than do mitochondria from younger cells.
Controlling Mitochondrial Damage [ Go to Page Top ]
Antioxidants
A number of naturally occurring compounds have antioxidant activity; they can scavenge and neutralize the potentially damaging oxidative compounds. Glutathione is one such antioxidant found in mitochondria. When glutathione is artificially depleted from cells, oxidative damage increases. The level of glutathione in mitochondria might be even more important than the level of glutathione in the rest of the cell. Mitochondrial glutathione levels diminish more with age than do the levels in the rest of the cell. This decline seems to make mitochondria more susceptible to oxidative damage.
Ascorbic acid, or vitamin C, is another naturally occurring antioxidant with protective powers. In aged cells, the activity of certain enzymes decreases in mitochondria. But in one study adding ascorbate to aged cells in a growth medium - in effect, "feeding" the cells vitamin C - reduced the rate of loss of these enzymes. Vitamin E, or tocopherol, is a third antioxidant known to help prevent the mitochondrial oxidative damage. Research has shown that overproduction of mitochondrial oxidants, with subsequent membrane damage, is observed in vitamin E-deficient cells.
Superoxide Dismutase (SOD)
Enzymes can also serve as antioxidants. Mitochondria contain an antioxidant enzyme called "superoxide dismutase" (SOD), which helps defang superoxide ions, an especially dangerous type of oxidant molecule. The importance of SOD in protecting mitochondria from oxidant damage was convincingly demonstrated in a study of animals genetically manipulated to produce half the normal amount of SOD. Increased oxidative damage was observed in the deficient mitochondria, along with alterations in their mitochondrial function. . A recent study published in the journal Investigative Ophthalmology and Visual Science (September 2001) looked at mice that were bred to be deficient in SOD. They were found to develop progressive thinning of the inner layers of their retinas as the result of having defective mitochondria.
DNA Repair
Scientists have known for a long time that nuclear DNA has an elaborate collection of enzymes that proofread and correct mistakes and gaps in the nucleic acid sequence. For many years, mitochondria were assumed to not be as fortunately endowed. However, mitochondria are now known to have the ability to repair some errors in their DNA. Preserving, and perhaps stimulating, this activity might be one means of preventing age-related deterioration in mitochondrial DNA.
The latest research on mitochondria and aging
The assertion that mitochondrial damage and disruption contribute to aging, and to a number of diseases that we associate with growing older, has gained wide acceptance among researchers. While our knowledge of the mechanisms that contribute to age-related mitochondrial damage is by no means complete, a fair amount is known about the generation of renegade oxygen free radicals - the compounds that indiscriminately damage components of the mitochondria. As a result of that understanding, current research on mitochondria and aging has tended to focus on several interrelated areas:
Minimizing the generation of compounds toxic to mitochondria
Neutralizing and protecting mitochondria from oxidants that are formedM
Repairing mitochondrial damage once it has occurred
Researchers are seeking to achieve these goals by testing various means, from modifying the diet to genetic manipulation.
Cellular Aging [ Go to Page Top ]
As normal cells approach the end of their ability to divide, they incur hundreds of biological changes that affect virtually all of their activities. Many of these changes are similar, if not identical, to the kinds of changes that we see occurring in aging humans themselves. Thus, the study of cellular senescence continues to provide important clues to the aging process at the most fundamental level--the cell.
Some of the senescent cells' functional losses appear to contribute to the aging process. For example, certain skin cells produce collagen during their younger, reproductive years. When they reach senescence and can no longer divide, they produce collagenase, an enzyme that breaks down collagen. Some researchers suggest that this process may be responsible for the thinning and wrinkling of skin as we age.
Some scientists also speculate that the growth arrest associated with replicative or reproductive senescence may retard the regeneration or repair of damaged tissue, which could play a role in the aging of the body.
From 1960 to 1990 the total US population grew by 30%, whereas the number of persons sixty-five years of age or older increased 89% and the number 85 years of age increased 232 %. (Bureau of Census. Current population report. 65 plus in America. Washington: US Government Printing Office; 1993).
In general, it appears that the process of aging involves a decline in the efficiency of various cells and tissues and systems. The real question is then what precipitates this decline in efficiency and can it be avoided. Memory impairment probably represents the most obvious change occurring both in the so-called physiological aging and in pathological aging.
One of the assumptions in biology is that normal cells can go through only a fixed number of divisions before they die, a process called senescence. The assumption leads to the conclusion that this accounts for the aging process. Harry Rubin, Professor of Molecular Biology at University of California, Berkeley wrote a review article in Mechanism of Aging and Development 1997; 98:1-35. The article entitled Cell aging in vivo and in vitro, presents evidence that cells "accumulate damage over a lifetime [that] results in gradual loss of differentiated function and growth rate". He rejects the notion of an intrinsic limitation of the number of cell divisions. It is the damage to cells over a lifetime that stimulates the effects of aging, which induces a gradual loss of differentiated function of the cells and growth rate. This stress (e.g. biochemical damage) on the cells reduces its capacity to multiply. It is not related to changes in hormonal states, blood flow or other system effects of aging. This is an important distinction for researchers to make in understanding what is aging. Reduce "the stress" and you prolong life.
Dr. Rubin believes that cells enter an altered stage of growth, due to stress, which renders them susceptible to cancer and other types of intrinsic events( caused or initiated by process that originates within the body) that can lead to death. Rubin states:"there is ample evidence for a decrease in stability of the genome with age which would help to account for the exponential increase in cancer with age. This does not rule out an additional need in many cases for multiple mutations to produce a fully autonomous cancer. More likely, both factors, and perhaps others, contribute to the age dependence of cancer incidence." What happens is that cells loss their capacity to control gene expression. It is this slowing down or loss that manifests itself as the aging process.
There are attempts by the body to deal with this process as result of the stabilizing feature of multcellularity in organs where metabolic cooperation among cells occurs. "Multicellularity also provides the opportunity for continuous selection of the least damage cells." (Rubin). The object then is to reduce the stress on cells to prevent the start of altered growth stages, manifested as aging.
It would seem that there is something in the architecture of the gene that relates in some way to longevity. Scientists have found that every chromosome has tails (telomeres) at its ends that get shorter as a cell divides. The telemere length is hypothesized to give some indication of how many divisions the cell has already undergone and how many remain before it becomes senescent. Is this the result of "stress" or a natural process? What would happen if we were able to stop this process? Continued cellular growth is seen in cancer where cells seem to be immortal. Is this the result of an abnormal gene product, telomere non-shrinkage, or other factors? Maybe if we understand the biochemistry of aging, we will have some of the answers, producing longer and healthier lives. The next part of this series will look at the healthy older person and what distinguishes that person from the rest of the population.
While the damage that occurs to DNA during life is postulated to play a large role in the processes of aging, less attention has been paid to the damage to other macromolecules, such as proteins, and the role it might play in aging. Scientists at the Robert Wood Johnson Medical School in New Jersey have published an article in the January 2002 issue of Mechanisms of Ageing and Development that looks at the role of protein damage and aging. They note that the progressive decrease in the creation of new proteins and the reduction in protein turnover are the primary reason for the presence of more damaged proteins as we age. They note that more protein damage might lead to even less protein turnover, and an accumulation of damaged proteins.
Caloric restriction slows the accumulation of damaged proteins, perhaps by reducing oxidative damage that causes that damage. Studies at the University of North Texas Health Science Center looked at caloric restriction in mice and its effect on protein damage. Older mice that had been maintained on a calorie restricted diet who were then freely fed reverted to levels of protein damage seen in those mice that had never been calorie restricted. Older mice changed over from a freely fed diet to a calorie restricted one showed lowered levels of protein damage. Thus, protein damage appears to be important in the aging process and the recognized benefits of calorie restriction in slowing the aging process have an impact on protein damage as well.
Physiological Changes and Symptoms in the Body During The Aging Process [ Go to Page Top ]
Nervous system
In aging, a diminished presence of neurotransmitters may predispose the elderly to depression and sleep disturbances. Changes in the central nervous system (i.e., decreased number of neurons, diminished neural glucose utilization) cause diminshed coordination and balance, changes in mental acuity and sensory interpretation, a lack of dexterity, difficulties in information retrieval, sleep, and alteration in mood.Gastrointestinal system
The elderly have an increased incidence of peptic ulcers, biliary tract disease, intestinal obstructions, and hiatal hernia. Worn and loose teeth cause difficulties in chewing. Poor appetite may result from the loss of taste buds and decreased olfactory function. Digestive disturbances may occur due to a thinning of the stomach mucosa and diminished enzyme and acid production. Constipation is often seen in the elderly because of lack of exercise, dehydration and low fiber diets. The aging population also has a higher percent of colon cancer.Musculoskeletal system
In the elderly there is a thinning of vertebra and intervertebral discs, increased thoracic curve and compensatory cervical curvature causing the characteristic stooped posture and tilted head. A reduction in lean (muscle) body mass and increased abdominal fat stores shifts the body composition of the elderly human body. Decreased bone mineral mass, weight loss, diminished muscle strength and joint mobility are all gross indicators of aging. In the elderly, resting tremor, degenerative arthritis (osteoarthritis), rheumatoid arthritis, fractures, osteoporosis, risk of falling and fracture, and degeneration of the joints are all common.Respiratory function
There is a loss of elasticity in the tissues (connective and epithelial) of the lung causing a decreased compliance, or stretch and elastic recoil of the lungs. Older persons breath more shallow and frequently causing the bases of the lungs are ventilated less and less. There is a concomitant decrease in arterial oxygen. The elderly also present with respiratory changes due to environmental pollutants or smoking. Pollutants decrease ciliary action, increase mucous production and decrease elasticity of the lungs.Cardiovascular function
With age there is an increase in peripheral vascular resistance due to decreased elasticity of the vasculature because of increased collagen and cross-linking of connective tissue elements. The increased vascular resistance causes increased blood pressure and sometimes a lack of adequate blood flow to the heart muscle thus causing angina or heart attacks. As a person ages atherosclerosis increases narrowing the lumen of the large vessels and predisposing them to aneurysms (ballooning) and possible rupture of the vessel. Arterial circulation to all organs including the brain and kidney is diminished. Immobilization and inactivity increases the risk of thrombosis and emboli. Pressure receptors become less responsive with age so that the effect of gravity in postural changes may cause dizziness or fainting.Genitourinary function
There is a loss of nephrons, the functional unit of urine formation in the kidney, with age. This causes a decrease in kidney mass, volume, and filtering surface area. These anatomical changes produce a general decline in function in that the kidneys do not concentrate the urine as well. Complications to kidney function in the elderly include dehydration, hemorrage, cardiac failure, systemic infection, the improper use of diuretics or toxic antibiotics. Incontinence and/or urinary frequency may be a result of loss of sphincter tone, a change in bladder reflexes, or decreased muscle tone in the female and an enlarged prostate in the maleSensory System
Most people will loose some sensory ability as they age. Sight, hearing, taste, smell and touch all suffer some loss which may contribute to isolation in the elderly. The lens of the eye may become less elastic leading to presbyopia. Cataracts may result if the lens looses its tansparency due to the accumulation of insoluble proteins. The incidence of glaucoma increases with age and, while it is easily treated, still accounts for 10% of the blindness in the US. Significant hearing loss can occur with the loss of high frequency sound being first followed by the loss of low frequency hearing. There is a decrease in the number of taste buds often affecting appetite and dietary intake of salt and sweets. Tactile sensation may decrease as well in the elderly predisposing them to burns and minor injuries. The sense of smell may also be diminished in the elderly.
Other Topics in the Biology of Aging [ Go to Page Top ]
Researchers are exploring several big questions about the aging process. Are there genes that grant us longevity? Can a drastically reduced diet improve and lengthen our lives? Can we learn something about human longevity from simple organisms like worms or fruit flies? Click below for more information and answers to these and other questions in the biology of aging.
Biomarkers of Aging Information Center [New!]
Are there tests that can predict how long a person will live?The Immune Response and Aging Information Center [New!]
Are there new vaccines and other immunological strategies that may help us ward off the disease of aging?Cloning and Aging Information Center [New!]
What might new cloning technologies mean for fighting age-related diseases and confronting the aging process?Neurobiology of Aging Information Center [New!]
How does the brain change with age?The Human Genome Project [New!]
What does the mapping of the human genome mean for aging research?Theories of Aging [Updated: May 2002]
How do we age?Longevity Assurance Genes [Updated: May 2002]
Are there specific genes that help people live to 100 and beyond?Caloric Restriction [Updated: August 2001]
Can drastically reducing our calories increase our longevity?Animal Models of Aging [Updated: May 2002]
What does research on other animals and organisms tell us about the human aging process?