Aging is accompanied by gradual changes in most body systems. Research on the biology of aging focuses on understanding the cellular and molecular processes underlying these changes as well as those accompanying the onset of age-related diseases. As scientists learn more about these processes, experiments can be designed to understand when and how pathological changes begin, providing important clues toward developing interventions to prevent or treat disease. A great deal has been learned about structural and functional changes that occur in different body systems. Research has expanded our knowledge, too, of the biologic factors associated with extended longevity in humans and animal models.
This section of the NIA's narrative discusses some recent advances in the biology of aging. It begins with a Story of Discovery about new insights into the genetic and molecular basis of longevity, and several new advances in extending the lifespan. A discussion of promising new avenues of stem cell research follows, along with several other important NIA-supported findings from the past year.
Extending the Lifespan
In order to understand the aging process, it is important to identify those factors that affect the overall lifespan of an organism. Understanding the responsible physiological mechanisms and, further, identifying ways to slow down age-related changes are important. Beyond any gains in lifespan, studies in this area are aimed more importantly at developing interventions to keep older people healthy and free of disease and/or disability as long as possible. Experiments in a number of animal models are providing valuable insights into the mechanisms of longevity.
Story of Discovery: Genetic and Molecular Basis of Longevity
Jeanne Calment of Arles, France is believed to have lived longer than any other person in recorded history. When she died on August 4, 1997, she was 122 years, 5 months, and 14 days old. What factors allowed her to live such a long life? Life expectancy in the United States has risen dramatically in the 20th century, from under 50 years in 1900 to about 73 for men and 79 for women in 1999; however, of the world's current 6 billion inhabitants, perhaps no more than 25 people are more than 110 years old.
Today, scientists believe that while Madame Calment's exceptional longevity may be partially attributable to her lifestyle, her genetic makeup almost certainly played a substantial role. Increasingly, evidence points to a significant genetic influence on longevity. In one recent study of four families with a high number of members surviving to 90 years or more, researchers found evidence of a familial cluster of longevity that cannot be explained by chance alone. Researchers in a second study found that exceptionally long-lived people may pass on to their children lifelong protection against major diseases of aging, including an unusually good pattern of circulating cholesterol, a major factor affecting risk of cardiovascular disease. And in a third study, investigators studying centenarians or near-centenarians and their siblings identified a portion of chromosome 4 on which they believe a gene for exceptional longevity may be located.
In fact, it is likely that heredity, environment, and lifestyle all have complex roles in determining a long and healthy life. But is there a maximum human lifespan beyond which we cannot live no matter how optimal our environment or favorable our genes? And perhaps, most importantly, how can insights into longevity be used to fight age-related diseases and disabilities to ensure a healthy, active, and independent life well into very old age?
Since the 1930s, investigators have consistently found that laboratory rats and mice live up to 30 percent longer than usual when fed a diet that has at least 30 percent fewer calories than they would normally consume, but is nutritionally balanced. This was the first demonstration that the maximum lifespan of a mammal could be increased. More recent research has found that these animals also appear to be more resistant to age-related diseases including cancer. Other rodent studies have found that caloric restriction may increase resistance of neurons in the brain to dysfunction and death. In fact, caloric restriction appears to delay normal age-related degeneration of a number of physiological systems in rodents.
Studies on the effects of caloric restriction in higher mammals (monkeys) are ongoing. Preliminary results are promising, including greater resistance to diabetes and heart disease in these animals. Yet even if caloric restriction is successful in extending primate lifespan, it is doubtful that it will ever become acceptable for most humans. However, caloric restriction shows that lifespan can be altered, prompting research into possible mechanisms.
Why calorically restricted animals live longer and have reduced rates of age-related diseases is still unclear. Over the years, scientists have approached this question by identifying and characterizing genes that modify the lifespan of various organisms including yeast, fruit flies, worms, and mice to determine which biological pathways are involved in lifespan extension and to determine if these same pathways may be affected by caloric restriction or other interventions. At least 15 different life-extending genetic manipulations have been identified in the past ten years in these organisms. These genetic manipulations pinpoint three metabolic systems: the cellular response to stress, especially oxidative stress; hormonal control; and processes like metabolic rate that are altered by caloric restriction.
Oxidative Stress. Oxidative stress, or damage to cells by metabolic by-products known as free radicals, is implicated in many of the processes of aging. Antioxidants, which can be nutrients such as vitamin E or compounds that are naturally produced within the body, combat oxidative stress by neutralizing free radicals. One particularly potent antioxidant is superoxide dismutase (SOD), an enzyme produced within the cell. High levels of anti-oxidants have been associated with longer lifespans in some model systems. Studies have shown that inserting extra copies of the gene for SOD production into fruit flies extends their average lifespan by as much as 30 percent, and researchers have found that giving C. elegans, a tiny worm with a very short lifespan, synthetic forms of antioxidants significantly extends their life. Interestingly, caloric restriction increases the resistance of organisms, including mice, to oxidative stress, again suggesting that there may be a relationship between stress resistance and aging.
Hormonal control. A major breakthrough occurred in 1995 when researchers discovered that mutations in certain genes in C. elegans can also substantially extend its lifespan. One of these genes, called daf-2, controls a special stage in the worm's development called dauer formation, a metabolically slowed, nonaging state that it enters when food is limited or there is overcrowding. Other investigators have detected mutations in similar daf genes that increase lifespan three-or even four-fold.
These genes are similar in structure to genes in humans for a protein that binds the hormone insulin to cells and for an enzyme involved in causing cellular changes in response—the so-called IGF-1 signaling pathway. The similarities suggest that worms also have an IGF-1-like signaling pathway, and that reducing its activity may increase their lifespan. In the late 1990s, researchers discovered that fruit flies also have such a pathway, and that mutations in the genes for this pathway also extend fruit fly lifespan.
Around the same time, a study showed a possible relationship between IGF-1 activity and longevity in mice. Dwarf mice have low levels of several hormones, including growth hormone, which normally stimulates production of IGF-1. These mice have low levels of IGF-1 and are also long-lived. Scientists recently found that mutations that stop growth hormone function in mice not only increase lifespan, but also delay the point at which the cell permanently stops dividing, suggesting an effect on the rate of aging as well as on lifespan. These results highlight the important influence of hormonal regulation on aging.
Metabolic Rate. A mutation in a gene affecting metabolism also increases lifespan in fruit flies. This mutation affects a protein that carries metabolic products of carbohydrates and fats called dicarboxylic acids into the energy factories of the cell, the mitochondria, where the dicarboxylic acids are converted into chemical energy. In flies with this mutation, the mitochondria have less access to dicarboxylic acid fuels and therefore lowered energy production, and the flies' life span is increased. This result may be a clue to one mechanism extending lifespan by calorie restriction as it is likely that caloric restriction would similarly restrict fuel available to mitochondria for conversion into energy.
Implications for Human Aging. The genes isolated so far in model systems are only a few of what scientists think may be dozens, perhaps hundreds, of longevity-and aging-related genes active in many different body pathways. The next big question is whether counterparts in people—human homologs—of the genes found in laboratory animals have similar effects. If they do, these ultimately could yield clues about how genes interact with environmental factors to influence longevity in humans. The outcome of this ongoing exploration of genetic and non-genetic factors affecting lifespan has been to show that aging is not as immutable as previously supposed, and that we may eventually be able to identify practical ways of extending active and healthy lifespan in humans.
The Promise of Stem Cell Research
Human pluripotent stem cells—that is, cells that are capable of dividing for indefinite periods in culture and of giving rise to most tissues of an organism—hold enormous potential for cell replacement or tissue repair therapy in many degenerative diseases of aging. For disorders affecting the nervous system, such as Alzheimer's and Parkinson's diseases, amyotrophic lateral sclerosis, and spinal cord and brain injury, transplantation of neural cell types derived from human pluripotent stem cells offers the potential of replacing cells lost in these conditions and of recovery of function. Human pluripotent stem cells can also provide a model for studying fundamental molecular and cellular processes important in understanding aging and age-related diseases. Another type of stem cell, multipotent or "adult" stem cells, are committed to producing cells that have a particular function. For example, stem cells circulating in the blood give rise to red blood cells, white blood cells, and platelets, but not bone cells or liver cells. Until recently, there was little evidence in mammals that multipotent cells could "change course" and produce cells of a different type. However, recent findings suggest that under certain conditions, some adult stem cells previously thought to be committed to the development of one line of specialized cells are able to develop into other types of specialized cells. Neural stem cells are of particular interest to the study of AD and other neurodegenerative diseases of aging. Through several recent studies, we have found that environmental cues, which vary among brain subregions, may determine the fate of a stem cell, that neurogenesis may require the cooperation of multiple protein factors, and that neural stem-like cells taken from post-mortem brain tissue can form neurons. Together, these studies continue to show the potential of adult-derived neural stem cells to make different kinds of brain cells.
Stem Cells Help Repair Damaged Heart and Brain. In the mouse, stem cells show potential to replace cells lost in either the heart or brain. When primitive bone marrow cells (a type of stem cell) are injected into the mouse circulatory system, they can find their way to the damaged brain and gradually change into neuronal cells. When bone marrow cells are transplanted into mouse hearts damaged by a "heart attack," these cells regenerate not only new heart muscle but also blood vessel components. In mice, this repair can be accomplished in just a few weeks. In a recent, highly provocative study, mice in which heart damage had been induced were injected with cytokines (proteins) called stem cell factor (SCF) and granulocyte-colony-stimulating factor (G-CSF). Stimulated by the cytokines, primitive bone marrow cells swarmed to the hearts, converted to several different types of cardiac cells, and contributed to repair of the damaged tissue, improving both the heart function and the survival of the treated mice. This finding, while preliminary, suggests that it may be possible to mobilize the body's own naturally-occurring stem cells to repair tissue damage and fight disease.
Gene Expression and Aging
Characterization and Functional Classification of 15,000 Mouse Genes. New technologies are providing answers to questions about how genes control cell and tissue function. Arrays of DNA for specific genes permit the comparison of tens of thousands of genes at one time, to determine which are turned on or off in a particular cell or condition. A collection of 15,000 mouse genes has been developed, with emphasis on inclusion of genes active in placenta and embryo development. To facilitate extensive use of this gene collection, the set (currently named the "NIA mouse 15K cloned gene set") has been made available as a resource to the scientific community. This collection has been distributed to more than 100 research institutions world-wide. Nearly complete sequences of each gene in the 15K gene set are also available; by comparing the sequence information with genes that have already been well studied, scientists may be able to determine the function of these genes in mice. The Institute has also developed the NIA Microarray Facility, which provides investigators with low-cost access to microarrays developed from the set and will also provide for collecting and analyzing the gene expression findings of multiple investigators.
Gene Required for Full Reproductive Lifespan in Women. One to three percent of women have premature ovarian failure (POF), going through menopause before age 40.10 In a number of these cases, a mutant gene is likely to be the cause, but until now no gene directly involved in regulating the time of menopause in women has been identified. Recently, researchers isolated a gene, FOXL2, that is mutated in this condition. FOXL2 is required to activate a number of other genes in the ovary. When the function of FOXL2 is reduced by a mutation, the number of follicles (eggs) in the ovary falls to a level too low to sustain a full reproductive lifespan. These findings reveal the first gene that is critically involved in determining the number of follicles in a woman's ovary; as more is learned about FOXL2's function, interventions that prevent or alleviate POF may be developed. In addition, an understanding of the genes that affect premature menopause will help in understanding the normal menopause process and its consequences.
- Coulam CB et al. Incidence of premature ovarian failure. Obstetrics and Gynecology 67: 604-606, 1986.