Theories of aging
Aging is the process of growing older and includes changes in both biology and psychology. Biology refers to the way the body functions. Psychology describes how the mind functions. How people age has to do with genetics, environment, and lifestyle over a lifetime. The process of aging is complex, and may derive from a variety of different mechanisms and exist for a variety of different reasons. Aging is a universal biological phenomea, at least amongst eukaryotic organisms. Yet the average lifespan within and between species can vary greatly. This suggests that both genetic and environmental factors contribute to aging. Theories that explain aging can generally be divided between the programmed and error theories of aging. Programmed theories imply that aging is regulated by biological clocks operating throughout the life span.
This regulation would depend on changes in gene expression that affect the systems responsible for maintenance, repair and defense responses. Error theories blame environmental insults to living organisms that induce cumulative damage at various levels as the cause of aging (e.g., DNA damage, oxygen radicals, cross-linking). One potential cause of senescence is the accumulation of mutations in DNA, eventually leading to the progressive loss of key genes. Another is the shortening of telomeres in the process of DNA replication during cell division.
One view is that it is due to a particular DNA programming that has the sole purpose to "clean" Earth from old genes and assure offspring better living conditions through benign mutations. One possible mechanism may be "senescence genes". Genes which have a deleterious effect on individual's fitness are selected against by natural selection. Mutations in these genes which postpone the deleterious effect of the gene to a later time in individual's life history reduce the effect of natural selection to the gene, because the selection has less time to act on it. If the gene doesn't have a negative effect until after the individual has reproduced, the gene may escape natural selection altogether, because when selection starts to affect the gene, it has already propagated to the next generation.
An alternative view of looking at this question is: why do humans live so long? No other primate has such an extended post-reproductive phase of life. The "grandmothering theory" of evolution holds that because humans can teach their young, there was an evolutionary advantage for groups of humans who had a few older survivors to teach and care for the young. There is no particular evidence for this theory.
The first genetic component of aging was first identified in the budding yeast Saccharomyces cerevisiae. Replicative yeast cell aging is defined as the number of cell division (daughter cells) that can be produced by any given mother cell. Calorie restriction in yeast results in lifespan extension (each mother cell can produce more daughter cells). The gene Sir2 was identified as a gene required for lifespan extension by calorie restriction, and yeast cells without sir2 have a decreased lifespan. Sir2 is a NAD+-dependent histone deacetylase, and is required for genomic silencing at three loci: the yeast mating loci, the telomeres and the ribosomal DNA (rDNA). Yeast replicative aging is caused by homolgous recombination between rDNA repeats; excision of rDNA repeats results in the formation of extrachromosomal rDNA circles (ERCs). These ERCs replicate and preferentially segregate to the mother cell during cell division, and are believed to result in cellular senescence by titrating away essential nuclear factors. Lately research on a worm called Caenorhabditis elegans has demonstrated that aging is in part regulated by genes. The worm's short life span can be increased by more than 200 percent through genetic engineering. For example, mutations that affect insulin-like signaling in worms, flies and mice are associated with extended lifespan. This planned-obsolescence theory focuses on the genetic programming encoded within our DNA. We are born with a unique genetic code, a predetermined tendency to certain types of physical and mental functioning, and that genetic inheritance has a great deal to say about how quickly we age and how long we live. To use a macabre analogy it's as though each of us comes into the world as a machine that is preprogrammed to self-destruct. Each of us has a biological clock ticking away set to go off at a particular time, give or take a few years. When that clock goes off it signals our bodies first to age and then to die.
However, as with all aspects of our genetic inheritance the timing on this genetic clock is subject to enormous variation, depending on what happens to us as we grow up and on how we actually live (the old "nature versus nurture" debate). Anti-aging medicine addresses this issue by augmenting the basic building blocks of DNA within each of our cells, preventing damage to and increasing repair of DNA. In this way we believe anti-aging treatment can help us escape our genetic destinies, at least to some extent.
The free radical theory
This exciting development in anti-aging research was first introduced by R. Gerschman in 1954, but was developed by Dr. Denham Harman of the University of Nebraska, College of Medicine. "Free radical" is a term used to describe any molecule that differs from conventional molecules in that it possesses a free electron, a property that makes it react with other molecules in highly volatile and destructive ways. In a conventional molecule the electrical charge is balanced. Electrons come in pairs so that their electrical energies cancel each other out. Atoms that are missing electrons combine with atoms that have extra electrons, creating a stable molecule with evenly paired electrons and a neutral electrical charge. The free radical on the other hand has an extra negative charge. This unbalanced electrical energy tends to make the free radical attach itself to other molecules as it tries to steal a matching electron to attain electrical equilibrium. Some scientist speak of these free radicals as "promiscuous," breaking up the happy marriages of paired electrons in neighboring molecules in order to steal an electron "partner" for themselves. In doing so they create free radicals and extensive bodily damage. Free-radical activity within the body is not only or even primarily negative. Without free-radical activity, that is without biochemical electricity, we would not be able to produce energy, maintain immunity, transmit nerve impulses, synthesize hormones or even contract our muscles. The body's electricity enables us to perform these functions and that electricity comes from the unbalanced electron activity of free radicals.
But free radicals also attack the structure of our cell membranes, creating metabolic waste products, including substances known as lipofuscins. An excess of lipofuscins in the body is shown as a darkening of the skin in certain areas, so-called "aging spots." Lipofuscins in turn interfere with the cells ability to repair and reproduce themselves. They disturb DNA and RNA synthesis, interfere with synthesis of protein, lower our energy levels, prevent the body from building muscle mass and destroy cellular enzymes, which are needed for vital chemical processes. This type of free-radical damage begins at birth and continue until we die. In our youth its effects are relatively minor since the body has extensive repair and replacement mechanisms that in healthy young people function to keep cells and organs in working order. With age however the accumulated effects of free-radical damage begin to take their toll. Free-radical disruption of cell metabolism is part of what ages our cells; it may also create mutant cells leading ultimately to cancer and death.
Free radicals attack collagen and elastin, the substances that keep our skin moist, smooth, flexible and elastic. These vital tissues fray and break under the assaults of free radicals, a process particularly noticeable in the face, where folds of skin and deep-cut wrinkles are testaments to the long-term effect of free-radical damage.
Another way of looking at free-radical changes is to think of its as oxidation, the process of adding oxygen to a substance. Another word for oxidation is rust and in a sense our aging process is analogous to the rusting away of a once-intact piece of metal. Because forms of oxygen itself are free radicals, our very breathing and our otherwise healthy aerobic exercise generate free radicals that help along the aging process. Substances that prevent the harmful effects of oxidation are known as antioxidants. Natural antioxidants include vitamin C, vitamin E and beta carotene, the substance that our body uses to produce vitamin A. Specialists in anti-aging medicine prescribe a host of natural and manufactured antioxidants to help combat the effects of aging.
Another substance that combats free-radical damage is known as a free-radical scavenger. Free-radical scavengers actually seek out free radicals and harmlessly bind them before they can attach themselves to other molecules and/or cause cross-linking. As we'll see in subsequent chapters many vitamins and minerals and other substances fight aging by acting as free-radical scavengers.
The wear and tear theory of aging
The wear and tear theory of aging suggests that years of damage to cells, tissues and organs eventually wears them out, killing them and then the body. The damage begins at the level of molecules within our cells. The DNA that makes up our genes sustains repeated damage from toxins, radiation and ultraviolet light. Our bodies have the capacity to repair DNA damage, but not all of those repairs are accurate or complete. Thus the damage progressively accumulates. Our mitochondria, the tiny "powerhouses" inside our cells that transform energy into useful form, are also susceptible to accumulated errors, and they have only a small capacity for repair. At the ends of our chromosomes are "caps" of DNA called telomeres, which shorten with each cell division. When they have reached a critically short length, the cells can no longer divide, but rather become senescent. Studies published in the August 2001 issue of the Journal of the American Geriatric Society have noted that loss of telomeres leads to DNA damage. Addition of the enzyme telomerase, which repairs shortened telomeres, to cell cultures, appears to maintain cells in a youthful state, perhaps by preventing some of the DNA damage that telomere shortening can cause. While the relationship between this inability to divide at the cellular level and broader aging at the organism level is not well characterized, these studies give indirect support to the wear and tear theories of aging.
Evidence to support the wear and tear theory of aging comes from insect observations. For example, few cells in the wing muscles of adult fruit flies reproduce, and while week-old fruit flies can fly 110 minutes without landing, month-old fruit flies must land after 19 minutes. Additional evidence comes from the accumulation of mitochondrial damage with aging in some insects. However, scientists point out that this wear and tear could easily be viewed as a result of aging and not a cause of it. Another argument against wear and tear as a major cause of aging is the fact that while some investigators report an age-related decline in the ability of certain animals (beagles, mice and rats) to repair their damaged or worn DNA, other scientists studying beagles, mice and hamsters did not observe such a decline.
Scientists at the University of Chicago looked at the effect of a lifetime of exposure to stress hormones such as cortisol, a naturally occurring steroid whose levels rise in our circulation under physically and emotionally stressful conditions. They note that circulating cortisol levels rise as we age. They also noted that while cortisol levels fall at night in younger adults, in older adults, the levels do not fall as far, increasing our exposure to high levels of cortisol. They speculate that the drop-off in variability of cortisol levels is due to the wear and tear of lifelong exposures to stress.
The cross-linking theory of aging
The cross-linking theory of aging is based on the observation that with age, our proteins, DNA and other structural molecules develop inappropriate attachments or cross-links to one another. These unnecessary links or bonds decrease the mobility or elasticity of proteins and other molecules. Proteins that are damaged or no longer needed are normally broken down by enzymes called proteases, and the presence of cross-linkages inhibits the activity of proteases. These damaged and unneeded proteins, therefore, stick around and can cause problems. Some research supports this theory. Cross-linking of the skin protein collagen has been shown to be at least partly responsible for wrinkling and other age-related changes in skin. Cross-linking of proteins in the lens of the eye is also believed to play a role in age-related cataract formation. Researchers speculate that cross-linking of proteins in the walls of arteries or the filtering systems of the kidney account for at least some of the atherosclerosis (once called hardening of the arteries) and age-related decline in kidney function observed in older adults. Another study conducted at the Bjorksten Institute in Wisconsin treated brain tissue from young animals with known cross-link-inducing compounds. That brain tissue soon looked quite similar to older brain tissue with its naturally cross-linked brain proteins, adding evidence in support of this theory of aging.
Somewhat indirect experimental evidence in support of the cross-linking theory of aging can be found in studies that look at drugs that prevent cross-linking, and the impact of taking those drugs on the various components of the aging process. Studies done in China and in the United Kingdom on the molecule carnosine are provocative. Carnosine occurs in very low concentrations in the brain and other tissues. In the laboratory, carnosine has been shown to delay the senescence or aging of human cells called fibroblasts. Carnosine works by preventing cross-linking of proteins.(4) The more recent Chinese studies suggest carnosine might be of benefit in delaying the formation of cataracts, in which cross-linking is thought to play a part.
Although many scientists agree that cross-linking of proteins, and perhaps the cross-linking of DNA molecules as well, is a component of aging, the lack of other direct experimental evidence at this time leaves many unconvinced that it is a primary cause of aging.
Lately the role of telomeres has aroused general interest, especially with a view to the possible genetically adverse effects of cloning. The successive shortening of the chromosomal telomeres with each cell cycle is also believed to influence the vitality of the cell, thus contributing to aging. There have, on the other hand, also been reports that cloning could alter the shortening of telomeres.
It is also suggested that damage to long-lived biopolymers, e.g., structural proteins and DNA, caused by ubiquitous chemical agents in the body, such as oxygen and sugars, are in part responsible for aging. The damage can include breakage of biopolymer chains, cross-linking of biopolymers, or chemical attachment of unnatural subtituents (haptens) to biopolymers. Oxygen spontaneously generates low levels of reactive oxygen species such as singlet oxygen, peroxides and superoxide ion, which can in turn generate free radicals which can damage structural proteins and DNA. Certain metal ions found in the body, such as copper and iron, may participate in the process. (In Wilson's disease, a hereditary defect which causes the body to retain copper, some of the symptoms resemble accelerated senescence.) These processes are termed oxidant damage and are the target of the currently popular nutritional antioxidants.
Sugars such as glucose and fructose can react with certain amino acids such as lysine and arginine and certain DNA bases such as guanine to produce sugar adducts, in a process called glycation. These adducts can further rearrange to form reactive species which can then cross-link the structural proteins or DNA to similar biopolymers or other biomolecules such as non-structural proteins. People with diabetes, who have elevated blood sugar, develop senescence-associated disorders much earlier than the general population, but can delay such disorders by rigorous control of their blood sugar levels. There is evidence that sugar damage is linked to oxidant damage in a process termed glycoxidation.
Chemical damage to DNA can lead to mutations (see above). Chemical damage to structural proteins can lead to loss of function; for example, damage to collagen of blood vessel walls can lead to vessel-wall stiffness and thus hypertension, and vessel wall thickening and reactive tissue formation (atherosclerosis); similar processes in the kidney can lead to renal failure.