ScienceWeek

GERONTOLOGY: ON AGING IN RHESUS MONKEYS

The following points are made by G.S. Roth et al (Science 2004 305:1423):

1) As gerontological research continues to gain both visibility and interest within the broader scientific community, the relevance of various model systems for eventual application of findings to humans has become a critical issue. Although rodents remain the most widely used animal model for gerontology, an increasing use of invertebrates has provided many new insights into aging processes, especially regarding possible longevity genes (1). Given the complexity of human physiology, however, models more phylogenetically similar to humans are needed.

2) Research using nonhuman primates can provide a valuable approach for elucidating the nature and causes of aging processes observed in humans as well as evaluating potential interventions. An ongoing longitudinal study of aging and nutrition in rhesus monkeys (Macaca mulatta) conducted since 1987 by the National Institute on Aging (NIA), as well as studies conducted at other sites, has revealed much about aging and age-related disease in these monkeys and has shed light on the advantages and disadvantages of their use in gerontological research. Because of their genetic homology to humans (92.5 to 95%), many biological similarities are observed in the profile of aging. Another advantage is that rhesus monkeys are well adapted for laboratory research, including established husbandry, nutrition, breeding practices, and veterinary medicine. Disadvantages of rhesus monkeys include their current limited availability, costs of procurement and maintenance, and genetic heterogeneity. In addition, cross-species risks of disease transmission exist, and issues of animal welfare require constant vigilance. Research in monkeys is only as good as their physical and emotional health.

3) The major scientific disadvantage is that rhesus monkeys are long-lived. Sexual maturity occurs at 3 to 5 years of age, median life-span is 25 years, and maximum life-span is 40 years (2,3). With an estimated maximum life-span of 122 years in humans (4), the rate of aging in rhesus monkeys is roughly three times as fast. Thus, rhesus monkeys offer a distinct advantage over long-term human aging research, but longitudinal studies in these primates require a major investment of time, resources, and effort.

4) Regarding morphology, physiology, and behavior, the profile of aging in rhesus monkeys is remarkably similar to human aging. Sensory systems decline in rhesus monkeys, including presbyopia (loss of near vision) and presbycusis (loss of high-frequency hearing). With advancing age, they lose accommodation of the lens and develop cataracts and macular degeneration. Regarding behavioral function, their general level of motor activity declines with age with gradual decrements in fine-motor skills. Advancing age does not generally affect simple discrimination learning abilities, but when demands are placed on working memory capacity, the clear age-related decline in learning and memory performance is notably similar to humans.

5) Age-related changes in physiological function include declines in metabolic rate and core body temperature. Age-related changes have not been reliably observed in cardiac function, including heart rate, blood pressure, or measures of arterial stiffness, but the possible contribution of dietary sodium to these age-related changes is currently being addressed. Regarding diet, another interesting parallel to humans is an apparent decline in appetite, manifested as a gradual decline in food intake.

6) Structural changes with aging are also evident in rhesus monkeys. Their stature becomes diminished, and bone mineral density in selected sites declines with age. Age-related changes in cartilage occur as reduced space between vertebrae, similar to osteoarthritis in humans.

7) Body composition in rhesus monkeys also parallels changes observed in humans. Their fat mass, particularly abdominal fat, increases with age, whereas lean body mass declines. Regarding skin quality, age-related deterioration in wound healing has been documented. At a biochemical level, glycation of rhesus skin proteins is similar to that in humans but occurs at a predictably faster rate. Age-related changes in the rhesus brain, hormone profiles, and immune system have also been studied, and many of these changes parallel those seen in humans. The National Institute of Aging supports colonies of aging rhesus monkeys at five primate research centers in the US.(5)

References (abridged):

1. A list of genes and their aging phenotypes is available at http://sageke.sciencemag.org/cgi/genesdb

2. R. J. Colman, J. W. Kemnitz, in Methods in Aging Research, B. P. Yu, Ed. (CRC Press, Boca Raton, FL, 1999), pp. 249-267

3. N. L. Bodkin, T. M. Alexander, H. K. Ortmeyer, E. Johnson, B. C. Hansen, J. Gerontol. Biol. Sci. 58A, 212 (2003)

4. More information about maximum human life-span is available at www.grg.org/calment.html

5. US NIA-supported primate research centers with colonies of aging rhesus monkeys include: Oregon Health Sciences University, Tulane University, University of California Davis, University of Washington, and University of Wisconsin

Science http://www.sciencemag.org

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Related Material:

MYTHS CONCERNING AGING

The following points are made by David Concar (New Scientist 2001 22 September):

1) Myth #1: Thanks to modern medicine and scientific advances, adults today can expect to live into their 70s or 80s, whereas our ancestors mostly died in early middle age. Reality: The great increase in average life expectancy at birth in the 20th century is primarily due to the great reduction in infant mortality. In actuality, many people in the 18th and 19th centuries lived into their 70s and 80s.

2) Myth #2: Given the health improvements and longevity gains of the 20th century, people may soon live routinely to 120 years. Reality: Again, the main apparent recent changes in longevity are due to changes in infant mortality rates. Only a small proportion of the longevity changes came from attacks on killer diseases of adults. According to death rate statistics, medical science would have to eliminate every single current common cause of human death merely to reach a life expectancy of 100.

3) Myth #3: Researchers can make worms and flies live much longer than normal, so some kind of treatment that will slow down aging in humans is inevitable. Reality: Nematode worms and flies are quite different from humans, and their use as "models" for aging research is questionable. For the most part, these animals have been useful in aging research because they have short lifespans, which makes experiments easier and faster. But this is also considered the major flaw of research into longevity: such research is based on animals that lack longevity. The evidence from aging research on longer-lived species does not support the idea that scientific manipulation of aging in humans is inevitable.

4) Myth #4: Human lifespan can be dramatically extended simply by ingesting protective antioxidant vitamins to improve the defenses of the body against free radicals. Reality: This is an overly optimistic idea. Free radicals are constantly produced in all biological cells, and virtually all organisms have natural antioxidants and enzymes to prevent DNA damage and other damage by free radicals. The problem is that there is no way that antioxidant supplements can remove all free radicals, and even if this could be accomplished it would probably damage the workings of the immune system, which apparently requires free radicals for some of its pathways. In general, experiments involving the use of free-radical quenchers that have produced some increase in longevity in lower animals have produced no increases or even decreases in mammals.

5) Myth #5: Semi-starved rats and mice live up to 50 percent longer, so humans should be able to live to 120 by reducing calorie intake. Reality: There is no hard evidence for this in humans. Caloric restriction experiments are now underway with monkeys, but it will be 10 years before the results are apparent. Meanwhile, severe caloric restriction in humans produces debilitation and disease, rather than longevity.

6) Myth #6: Growth hormone supplements can help forestall aging. Reality: There is no evidence to support this idea, and in fact recent evidence suggests that people with lower growth hormone levels live longer, and that growth hormone supplements have serious side effects.

7) But despite the realities above, there are certainly puzzles that need to be solved by research. Okinawa, a chain of islands stretching from Japan to Taiwan, has 1.3 million people in a population with the longest life expectancy on the planet, with 4 times the percentage of centenarians found in Western countries. Researchers are currently attempting to determine the factors (diet, lifestyle, genetics, etc.) responsible for Okinawa's vital statistics.

New Scientist http://www.newscientist.com

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Related Material:

AGING: CALORIC RESTRICTION AND LONGEVITY

The following points are made by J.W. Vaupel et al (Science 2003 301:1679):

1) Experiments in species as diverse as yeast, worms, flies, and rodents demonstrate that dietary restriction prolongs survival. Mair et al (1) have revealed that a lifetime of abstemiousness is not required to reduce one's risk of death -- at least in fruit flies. These researchers demonstrated that when flies fed a restricted diet are switched to a full diet, mortality soars to the level suffered by fully fed flies. Conversely, when the diet of fully fed Drosophila is restricted, mortality plunges within 2 days to the level enjoyed by flies that have experienced a lifelong restricted diet.

2) The alliterative title of the Mair et al. paper -- "Demography of Dietary Restriction and Death in Drosophila" -- gives due credit to demography as the source of their new discovery. Demographers have long realized that death rates provide age-specific information that cumulative survival curves cannot (2). Heeding this insight, Mair et al. analyzed the daily mortality of their fed and hungry flies. Demography offers a further lesson: Death of the frail alters the composition of a cohort, lowering subsequent mortality and possibly offsetting increases in mortality resulting from cumulative damage (3).

3) Replication and refinement of the Mair et al experiments, especially in rodents, the principal animal model of dietary-restriction studies, will be a research priority. Rodent and Drosophila dietary-restriction experiments differ in two key respects. First, rodents in these experiments cannot mate or produce offspring because they are maintained in solitary confinement or in same-sex cages. Mair et al allowed their flies to mate before separating them into containers holding approximately 100 females or 200 males. They did not report egg production, but it seems likely that fully-fed females lay many eggs whereas females on restricted diets lay few (4). Even in all male containers, fully-fed males may have engaged in behavior associated with attracting females (such as courtship songs composed of wing vibrations) to a greater extent than males on restricted diets. Hence, the Mair et al findings could be due to a switch in and out of costly reproductive activity, but evidence for this will require further study.

4) Second, in rodent experiments, diets are restricted by reducing food quantity (generally to 60% or ad libitum), whereas in Drosophila experiments, the effect is achieved by reducing food quality. In their study, Mair et al. cut the yeast and sugar content of the fly diet to about 43% of that in standard laboratory medium. Other work in Mediterranean fruit flies (medflies) (5) demonstrates that reductions in food quantity do not increase longevity, whereas reductions in food quality do. A key uncertainty is whether quantity- or quality-restricted diets or ad libitum diets mimic conditions in the wild.

References (abridged):

1. W. Mair, P. Goymer, S. D. Pletcher, L. Partridge, Science 301, 1731 (2003)

2. J. W. Vaupel et al., Science 280, 855 (1998)

3. J. W. Vaupel, A. I Yashin, Am. Stat. 393, 176 (1985)

4. T. P. Good, M. Tatar, J. Insect Physiol. 47, 1467 (2001)

5. J. R. Carey, Longevity: The Biology and Demography of Life Span (Princeton Univ. Press, Princeton, NJ, 2003)

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