Richard A. Miller

Changes in T lymphocyte populations underlie much of the age-related decline in the protective immune response. Aging leads to the replacement of virgin T cells by memory T cells and to the accumulation of cells with signal transduction defects. Studies of antibody gene assembly, accessory cell function, post-thymic T cell development, skewed selection of T cell receptor repertoire, and the clinical concomitants of immune senescence will shed new light on the causes and consequences of age-dependent immune failure.

A GENTSthatcanextendthe lifespanofmiceareof interestfortworeasons:theycanprovidenewmodels of delayed aging to teach us more about what controls agingrateandhowagingleadstodisease;andinaddition, they serve as a first step toward eventual development of pharmaceuticals to slow aging and retard diseases in humans. The National Institute on Aging Intervention Testingprogram(ITP)haspreviouslyreportedsignificant increases in life span caused by aspirin and nordihydroguaiareticacid inmalemice(1)andbyrapamycinin bothmaleandfemalemice(2).ThedesignoftheITP(3) emphasizestheuseofgeneticallyheterogeneousmiceto mitigate against idiosyncrasies that can complicate inter-pretationofdatafromasingleinbredorF1hybridstock andincludesparallelreplicationofprotocolsatthreesites, the University of Texas (UT), University of Michigan (UM), and The Jackson Laboratory (TJL), with standard operatingprotocolsthatattempttoreproducekeyelements of the environmental conditions at each site. Sufficient numbers of mice are used in each yearly cohort to give morethan80%powertodetectanincreaseordecreaseof 10%inmeanlifespan,withrespecttocontrolsofthesame sex,evenifonlytwoofthethreesitescancontributedata tothepooledanalysis.

Single-gene mutations that extend lifespan provide valuable tools for the exploration of the molecular basis for age-related changes in cell and tissue function and for the pathophysiology of age-dependent diseases. We show here that mice homozygous for loss-of-function mutations at the Pit1 (Snell dwarf) locus show a >40% increase in mean and maximal longevity on the relatively long-lived (C3H/HeJ x DW/J)F(1) background. Mutant dw(J)/dw animals show delays in age-dependent collagen cross-linking and in six age-sensitive indices of immune system status. These findings thus demonstrate that a single gene can control maximum lifespan and the timing of both cellular and extracellular senescence in a mammal. Pituitary transplantation into dwarf mice does not reverse the lifespan effect, suggesting that the effect is not due to lowered prolactin levels. In contrast, homozygosity for the Ghrhr(lit) mutation, which like the Pit1(dw) mutation lowers plasma growth hormone levels, does lead to a significant increase in longevity. Male Snell dwarf mice, unlike calorically restricted mice, become obese and exhibit proportionately high leptin levels in old age, showing that their exceptional longevity is not simply due to alterations in adiposity per se. Further studies of the Pit1(dw) mutant, and the closely related, long-lived Prop-1(df) (Ames dwarf) mutant, should provide new insights into the hormonal regulation of senescence, longevity, and late life disease.

A diet deficient in the amino acid methionine has previously been shown to extend lifespan in several stocks of inbred rats. We report here that a methionine-deficient (Meth-R) diet also increases maximal lifespan in (BALB/cJ x C57BL/6 J)F1 mice. Compared with controls, Meth-R mice have significantly lower levels of serum IGF-I, insulin, glucose and thyroid hormone. Meth-R mice also have higher levels of liver mRNA for MIF (macrophage migration inhibition factor), known to be higher in several other mouse models of extended longevity. Meth-R mice are significantly slower to develop lens turbidity and to show age-related changes in T-cell subsets. They are also dramatically more resistant to oxidative liver cell injury induced by injection of toxic doses of acetaminophen. The spectrum of terminal illnesses in the Meth-R group is similar to that seen in control mice. Studies of the cellular and molecular biology of methionine-deprived mice may, in parallel to studies of calorie-restricted mice, provide insights into the way in which nutritional factors modulate longevity and late-life illnesses.