An Aging Interventions Testing Program: study design and interim report.

The National Institute on Aging's Interventions Testing Program (ITP) has developed a plan to evaluate agents that are considered plausible candidates for delaying rates of aging. Key features include: (i) use of genetically heterogeneous mice (a standardized four-way cross), (ii) replication at three test sites (the Jackson Laboratory, TJL; University of Michigan, UM; and University of Texas, UT), (iii) sufficient statistical power to detect 10% changes in lifespan, (iv) tests for age-dependent changes in T cell subsets and physical activity, and (v) an annual solicitation for collaborators who wish to suggest new interventions for evaluation. Mice in the first cohort were exposed to one of four agents: aspirin, nitroflurbiprofen (NFP), 4-OH-alpha-phenyl-N-tert-butyl nitrone (4-OH-PBN), or nordihydroguiaretic acid (NDGA). An interim analysis was conducted using survival data available on the date at which at least 50% of the male control mice had died at each test site. Survival of control males was significantly higher, at the interim time-point, at UM than at UT or TJL; all three sites had similar survival of control females. Males in the NDGA group had significantly improved survival (P = 0.0004), with significant effects noted at TJL (P < 0.01) and UT (P < 0.04). None of the other agents altered survival, although there was a suggestion (P = 0.07) of a beneficial effect of aspirin in males. More data will be needed to determine if any of these compounds can extend maximal lifespan, but the current data show that NDGA reduces early life mortality risks in genetically heterogeneous mice at multiple test sites.

Is cell death and replacement a factor in aging?

The central theme of the 3rd International Conference on Functional Genomics of Ageing was tissue regeneration as a remedial strategy to address age-related cellular damage and the pathology that ensues. The conference included sessions on maintaining genome integrity and the potential of stem cells to restore function to damaged tissues. In addition to several human syndromes that appear to reflect accelerated ageing, there are now a number of mouse models that prematurely display phenotypes associated with ageing. The intent of this summary presented at the end of the conference was to: (1) discuss various human syndromes and mouse models of accelerated ageing; (2) evaluate whether the phenotypes displayed might result from an elevated rate of cell death coupled with an inability to adequately maintain cell number in various tissues with increasing age; and (3) discuss whether similar events may be occurring during normal ageing, albeit much more slowly.

2006 Kent award lecture: is cell death and replacement a factor in aging?

This article briefly summarizes the Kent Award Lecture I gave at the annual meeting of The Gerontological Society of America held in Dallas, Texas, in November 2006. Cell death is a normal response of cells to cytotoxic damage due to both internal and external threats, and this cell loss is normally countered by proliferation of neighboring cells and/or replacement of these cells from progenitor cell pools. Maintaining tissue homeostasis is a critical challenge during aging, and this article describes a few aspects of the dynamic cell turnover that occurs continuously in vivo, with particular reference to the adverse effects of mutations that accelerate cell death through dysfunctional DNA metabolism, and how these events might contribute to aging in general.

Time, damage, and aging: what really matters?

This presentation was one of three short talks in the introductory session at the 2007 Edmonton Aging Symposium titled "The Damage of Aging: Present and Future Therapies." This title implies that if we can document what biological damage occurs with increasing age, then by either preventing, reducing or repairing this damage, we could intervene to delay the onset and severity of the adverse age-related phenotypes that accompany aging, and perhaps increase life span as well. While this assumption seems quite reasonable, some recent results suggest that this approach is not as straightforward as it might seem.

Scientific and ethical concerns regarding engineering human longevity.

The goal of biogerontological research is to elucidate the biological factors underlying adverse age-related changes in structure and function of molecules, cells, tissues, and organisms. In spite of the considerable progress achieved so far, it is still too early to predict what strategies will be both safe and effective at preventing, delaying, or reversing these changes in humans, and whether such strategies will also increase longevity.

Longevity genes: from primitive organisms to humans.

Recent results indicate that the longevity of both invertebrates and vertebrates can be altered through genetic manipulation and pharmacological intervention. Most of these interventions involve alterations of one or more of the following: insulin/IGF-I signaling pathway, caloric intake, stress resistance and nuclear structure. How longevity regulation relates to aging per se is less clear, but longevity increases are usually accompanied by extended periods of good health. How these results will translate to primate aging and longevity remains to be shown.

Developing a research agenda in biogerontology: basic mechanisms.

The National Institute on Aging (NIA) began operation in 1975, splitting off from the National Institute of Child Health and Human Development. The first 10 years of NIA's existence were characterized by funding descriptive and discovery research, as the field by then had not come of age. With the isolation of long-lived animal mutants and the application of the tools of molecular biology (including whole-genome sequencing) and transgenic technology to biogerontology research, the situation has changed dramatically since then, and aging-related research has become increasingly mechanistic and respectable. This transition has been aided by research initiatives implemented by NIA staff, and the goal of this article is to describe how NIA develops such research initiatives using research progress made in biogerontology over the past 20 years as the basis for the discussion.

Twenty years of progress in biogerontology research.

The first 10 years of NIA's existence were characterized by funding for descriptive and discovery research, as the field had not yet come of age. As Couzin expressed it in the July 1, 2005 issue of Science, "Just 2 or 3 decades ago, research on aging was a backwater" (Couzin J 2005 How much can human life span be extended. Science 309: 83). With the isolation of long-lived animal mutants and the application of the tools of molecular biology and transgenic technology to biogerontology research, the situation has changed dramatically since then, and aging research has become increasingly mechanistic and respectable. This transition has been aided by some well-thought out research initiatives by the NIA, and the purpose of this article is to provide a brief summary of the progress made in the past 20 years, and describe the part that NIA initiatives and funding have played in this transition.

NIA's Intervention Testing Program at 10 years of age.

The previous 20 years of basic research on aging has identified a large number of genes and gene products whose expression can be manipulated in a variety of ways to increase the healthy life span of animal models such as yeast, nematodes, fruit flies, and mice. In an overt attempt to capitalize on this information, the National Institute on Aging (NIA) began a program in 2003 to identify nutritional and pharmaceutical interventions that could be safely employed to extend the healthy life span of mice. This program is called the Intervention Testing Program (ITP), and this article briefly describes the development of this initiative and some of the early success achieved during its first 10 years (2004-2014) of operation.

Models of accelerated ageing can be informative about the molecular mechanisms of ageing and/or age-related pathology.

During the past ten years considerable progress has been made in discovering genes that regulate longevity by identifying single gene mutations that lead to increased longevity. The initial success in nematodes was quickly followed by comparable success in fruit flies and mice. In contrast, mutations that cause a decrease in longevity have been largely discounted as unlikely to be informative about aging mechanisms. However, the recent creation of several mutant mouse models that develop a variety of aging-like phenotypes and die prematurely, suggests that such models may be useful in understanding aging mechanisms, particularly as they relate to progressive tissue and organ dysfunction. A possible common feature of these models may be an imbalance between loss of cells by apoptosis and subsequent cell replacement, leading gradually to a net loss of cells in multiple tissues.

Current status of efforts to measure and modulate the biological rate of aging.

Biomarkers of aging would be highly desirable, but so far, a definitive panel of biomarkers to predict mortality risk has not been obtained, even though many traits that vary with age have been identified. This lack hinders the search for interventions that may retard the rate of aging in mammals. The recent discovery and characterization of many longevity genes in animal model systems, such as nematodes, fruit flies, and mice, are providing new targets for research by providing insight into mechanisms of longevity regulation in these model systems. It is hoped that this will ultimately lead to interventions to delay the development of age-related pathology in humans.

Is there an antiaging medicine?

In spite of considerable hype to the contrary, there is no convincing evidence that currently existing so-called "antiaging" remedies promoted by a variety of companies and other organizations can slow aging or increase longevity in humans. Nevertheless, a variety of experiments with laboratory animals indicate that aging rates and life expectancy can be altered. Research going back to the 1930s has shown that caloric restriction (also called dietary restriction) extends life expectancy by 30-40% in experimental animals, presumably at least partially by delaying the occurrence of age-dependent diseases. Mutations that decrease production of insulin growth factor I in laboratory mammals, and those that decrease insulin-like signaling in nematodes and fruit flies, have increased life expectancy as well. Other general strategies that appear promising include interventions that reduce oxidative stress and/or increase resistance to stress; hormone and cell replacement therapies may also have value in dealing with specific age-related pathologies. This article reports the findings of a consensus workshop that discussed what is known about existing and future interventions to slow, stop, or reverse aging in animals, and how these might be applied to humans through future research.

Biomarkers of aging: from primitive organisms to humans.

Leading biologists and clinicians interested in aging convened to discuss biomarkers of aging. The goals were to come to a consensus, construct an agenda for future research, and make appropriate recommendations to policy makers and the public-at-large. While there was not total agreement on all issues, they addressed a number of questions, among them whether biomarkers can be identified and used to measure the physiological age of any individual within a population, given emerging information about aging and new technological advances. The hurdles to establishing informative biomarkers include the biological variation between individuals that makes generalizations difficult; the overlapping of aging and disease processes; uncertainty regarding benign versus pathogenic age-related changes; the point at which a process begins to do damage to the organism, and, if so, when does it occur; and when to distinguish critical damage from noncritical damage. Finally, and significantly, it is difficult to obtain funding for this research.

Recent progress in understanding the relationships among aging, replicative senescence, cell turnover and cancer.

The link between aging and cancer is more than just the increasing accumulation of mutations with time. Recent research provides evidence that senescent cells are not merely passive bystanders, but may promote cancer through degradation of the tissue microenvironment. Another critical factor in the relationship between aging and cancer is p53 function; its activity level is apparently finely tuned to suppress cancer while regulating both apoptosis and the replacement of damaged cells through stem cell proliferation. The deacetylase activity of the sir2 gene product plays a role in longevity regulation in invertebrates, and also regulates p53 function in mammals, implying yet another link between aging and cancer in mammals.

Subfield history: use of model organisms in the search for human aging genes.

The National Institute on Aging (NIA) started a program in 1993 to identify genes involved in the regulation of longevity in a variety of species, including yeast, nematodes, fruit flies, and mice. The initial success of this program has attracted the interest of many investigators working with these organisms. Of primary interest are single-gene mutants that have identified genes and processes involved in longevity regulation across species. These processes include the insulin-like signaling pathway, stress resistance, and most recently, chromosome and nuclear architecture. Mutations in genes that regulate these processes indirectly are also being identified in this program. The ultimate goal of this program is to extend these results to humans to identify the major biological risk factors for age-related decline of function in human physiological systems.

Meeting report--National Institute on Aging Workshop on the Comparative Biology of Aging.

This Perspective is a summary of the Comparative Biology of Aging Workshop that was held in February 2002 by the National Institute on Aging in Bethesda, MD. Participants discussed ways to exploit similarities and differences in aging among diverse species to learn more about critical factors that affect aging and regulate life expectancy in animals. The aim of the workshop was to stimulate new approaches to understanding the molecular bases for differences in aging rates and life expectancy among species.