There may be no Shangri-La or fountain of eternal youth, but that does not stop scientists from searching for that biochemical reaction or signal transduction pathway that may hold the key to a longer and healthier "old age." A special section in the current Science reviews what is known about the aging process, placing particular emphasis on what model systems have taught us.

In organisms as diverse as yeast, roundworms, insects, and mammals, vastly different lifespans seem to be regulated by strikingly similar hormones, genes, and environmental factors. In the case of the last, the most important influence may well be diet. The current wealth of evidence linking caloric restriction (CR) to increased lifespan and prevention of disease, including Alzheimer's disease (see ARF related news story), prompted Valter Longo and Caleb Finch from the University of Southern California to review the impact of calories on health and longevity. They reveal that the effects of CR can be paralleled by mutations in glucose or insulin-like growth factor (IGF) pathways in yeast, worms, and flies. In mice, mutations that lead to dwarfism, but also extend lifespan by as much as 65 percent, are similarly linked in that they cause IGF deficiency. Indeed, in the latter case, the authors mention "preliminary data that the longevity effect of dwarf mutations can be separated from the small body size," leading them to propose a class of drugs that may postpone age-related diseases by preventing the release or activity of IGF.

Brown University's Marc Tatar and colleagues expand on the link between insulin-like peptides and longevity. While in worms and flies the evidence suggests that "secondary hormones downstream of insulin-like signaling appear to regulate aging," they write, in mammals the situation is more complex because growth hormone, thyroid hormones, and IGFs are all interdependent. However, Tatar and colleagues point out some strong evidence linking IGF with aging in mammals: Longevity is increased in mice with inactive insulin receptors in their adipose tissue (see ARF related news story), and IGF receptor mutations increase longevity in female mice by 33 percent, and enhance their tolerance to oxidative stress.

Indeed, oxidative stress has long been touted as a major player in both aging and neurodegenerative diseases. It, too, is coupled to metabolism through reactive oxygen species (ROS) generated by the respiratory chain. Siegfried Hekimi, McGill University, Montreal, and Leonard Guarente, MIT, review proteins of the respiratory chain that have a significant impact on longevity. In roundworms, for example, mutations in the electron transport protein Rieske reduce respiration and the generation of ROS, but considerably increase the lifespan of the worm. The interplay among calories, respiration, and longevity doesn't stop there, however. As described in today's review, Guarente's lab was the first to associate respiration rate with regulation of transcription through the NAD+-sensitive histone deacetylase, Sir2 (see ARF related news story). The co-factor NAD+ is reduced to NADH by electrons passing down the respiratory chain. Less respiration due to caloric restriction, for example, causes an increase in the NAD+/NADH ratio, leading to activation of Sir2 and ultimately, the silencing of transcription due to deacetylation of histones; in both yeast and worms increasing expression of Sir2 increases lifespan.

ROS are problematic because they can damage cellular macromolecules, most importantly, DNA. Evolution has ensured that a pool of DNA repair enzymes is on hand to correct such errors, but occasionally some go unchecked. What role does such damage have, if any, in aging? Probably quite a lot, reveals Paul Hasty from the University of Texas Health Science Center, San Antonio, and colleagues, who examine the relationship between age and integrity of the genome. The authors focus on a group of syndromes that result in premature aging in humans. Most of these "human segmental progeroid syndromes" have associated defects in DNA repair, or transcription, though for some, such as Hutchinson-Gilford syndrome, which has a mean life-expectancy of only 13 years, such an association has not yet been made. In mouse models, too, mutations or knockouts of DNA repair enzymes lead to premature aging. "Accelerated aging symptoms in humans and mice with genetic defects in genome maintenance strongly suggest that genome instability is a primary cause of normal aging," according to the authors.

Finally, a word of warning and a call for public debate from bioethicist Eric Juengst and colleagues at Case Western Reserve University, Cleveland. They suggest that, though improbable, research into aging may lead to attempts to arrest it, and that a mean life expectancy of 112 for Caucasian American and Japanese women has been proposed. Juengst and colleagues raise some interesting ethical questions, including, "Is aging, as we have known it, a human experience to be encouraged or discouraged?" and they suggest that "the NIH has a responsibility to help society respond to the implications of antiaging research for which it has been providing its cachet and public funds."—Tom Fagan.

References:
Longo VD, Finch CE. Evolutionary medicine: from dwarf model systems to health centenarians. Science. 2003 February 28;299:1342-1346. Abstract

Tatar M, Bartke A, Antebi A. The endocrine regulation of aging by insulin-like signals. Science. 2003 February 28;299:1346-1350. Abstract

Hekimi S, Guarante L. Genetics and the specificity of the aging process. Science. 2003 February 28;299:1351-1354. Abstract

Hasty P, Campisi J, Hoeijmakers J, van Steeg H, Vijg J. Aging and genome maintenance: lessons from the mouse? Science. 2003 February 28;299:1355-1359. Abstract

Juengst ET, Binstock RH, Mehlman MJ, Post SG. Aging. Antiaging research and the need for public dialogue. Science. 2003 Feb 28;299(5611):1323. Abstract

For extensive coverage of this special section, see also SAGE KE

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References

News Citations

  1. Fat and Calories Mean Higher AD Risk
  2. Lean Mice Live Longer: Does Insulin in Fat Hasten Aging?
  3. How Does Calorie Restriction Extend Life?

Paper Citations

  1. . Evolutionary medicine: from dwarf model systems to healthy centenarians?. Science. 2003 Feb 28;299(5611):1342-6. PubMed.
  2. . The endocrine regulation of aging by insulin-like signals. Science. 2003 Feb 28;299(5611):1346-51. PubMed.
  3. . Genetics and the specificity of the aging process. Science. 2003 Feb 28;299(5611):1351-4. PubMed.
  4. . Aging and genome maintenance: lessons from the mouse?. Science. 2003 Feb 28;299(5611):1355-9. PubMed.
  5. . Aging. Antiaging research and the need for public dialogue. Science. 2003 Feb 28;299(5611):1323. PubMed.

External Citations

  1. SAGE KE

Further Reading

Papers

  1. . Evolutionary medicine: from dwarf model systems to healthy centenarians?. Science. 2003 Feb 28;299(5611):1342-6. PubMed.

Primary Papers

  1. . Evolutionary medicine: from dwarf model systems to healthy centenarians?. Science. 2003 Feb 28;299(5611):1342-6. PubMed.