This article presents a conceptual discussion of some aspects involved in biomarkers of aging. A biomarker of aging is a biological parameter of an organism that either alone or in some multivariate composite will, in the absence of disease, better predict functional capability at some late age than will chronological age. The reasons for undertaking biomarker research, criteria for putative biomarkers, measurement and assessment of putative biomarkers, and the new initiative by the National Institute on Aging in biomarker research are discussed.

A long-lived (L) strain of Drosophila melanogaster, derived from a normal-lived (R) strain by artificial selection, has a significantly different adult longevity. Previous work has shown that 1) the two strains age in the same manner, 2) the major genes responsible for much of the L strain's extended longevity are located on the 3rd chromosome, and 3) the extended longevity phenotype is significantly modulated by the larval environment. In this report, we investigate the resistance of the L and R strains to the lethal effects of dietary paraquat. We show that, within the limitations of our described chromosomal and environmental manipulations, the extended longevity phenotype always accompanies the phenotype of elevated paraquat resistance. In addition, reversed selection applied to the L strain results in the simultaneous decrease of both life span and paraquat resistance. Thus, the presence or absence of the latter phenotype may be used as a bioassay for the presence or absence of the extended longevity phenotype, without any necessary implication of causality. Use of this bioassay should greatly speed up the genetic analysis of this system by allowing us to identify long-lived animals at a young age. Finally, we show that the age-related loss of elevated paraquat resistance in both strains precedes all the other age-related functional decrements which we have previously noted in this system.

A controlled chromosome substitution experiment was performed on a strain (NDC-L) selected for long life to determine if the genes responsible for the extended-longevity phenotype could be localized to any particular chromosome(s). All 27 different possible combinations of the three major chromosomes of Drosophila melanogaster were constructed and longevities were determined on 3875 individual animals of both sexes and analysed. The results are statistically significant and demonstrate that mean longevity is specified primarily by recessive genes on the third chromosome (c3). The extended longevity phenotype (ELP) is only expressed in those lines which are homozygous for the NDC-L type c3. Loci on the first (ci) and second (c2) chromosomes interact, both positively (ci) and negatively (c2), respectively, such that ci represses c2 which in turn represses c3. The ELP is fully expressed in the mutual presence and mutual absence of ci and c2. The significance of these results is discussed in the context of broader categories of molecular genetic mechanisms suggested previously to be involved in the modulation of longevity in Drosophila.

Aging is characterized by numerous physical, physiological, biochemical, and molecular changes. The rates at which aging processes occur are highly variable among individuals and are thought to be governed by both environmental and genetic factors. Lifestyle factors such as exercise, dietary, and smoking habits have been demonstrated to alter many of the changes usually associated with human aging. However, at present caloric restriction is the only experimental paradigm that has consistently been demonstrated in animal models to extend not only physiological vigor but also life span. The positive effects of exercise on physiological fitness and the reduction in the risks of certain diseases have been well documented. However, its effects on life span are not as clear. This article explores some of the basic mechanisms thought to be involved causally in the processes of aging, and outlines current and potential interventive strategies to retard or ameliorate the rates of decline in physiological function with advancing age.

Our previous work has shown that the major genes involved in the expression of the extendedlongevity phenotype are located on the third chromosome. Furthermore, their expression is negatively and positively influenced by chromosomes 2 and 1, respectively. In this report we show that the expression of the extended-longevity phenotype is dependent on the larval environment. A controlled chromosome substitution experiment was carried out using a strain selected for long life (L) and its parent (R) strain. Twenty different combinations of the three major chromosomes were conducted and their longevities were determined under both high (HD) and low (LD) larval density conditions. The extended-longevity phenotype was only expressed under RD conditions. The chromosome interactions were not apparent under LD conditions. Density-shift experiments delineate a critical period for expression of the extended-longevity phenotype, extending from 60 h after egg laying (AEL) to 96 h AEL, during which the developing animal must be exposed to HD conditions if the extended-longevity phenotype is to be expressed. The change from HD to LD conditions is accompanied by statistically significant increases in body weight. The possible role of a dietary restriction phenomenon is examined and the implications of these findings discussed. It is now apparent, however, that the extended-longevity phenotype in Drosophila is a developmental genetic process.