Big mice die young: early life body weight predicts longevity in genetically heterogeneous mice

Small body size has been associated with long life span in four stocks of mutant dwarf mice, and in two varieties of dietary restriction in rodents. In this study, small body size at ages 2-24 months was shown to be a significant predictor of life span in a genetically heterogeneous mouse population derived from four common inbred mouse strains. The association was strongest for weights measured early in adult life, and somewhat weaker, though still statistically significant, at later ages. The effect was seen both in males and females, and was replicated in an independent population of the same genetic background. Body size at ages 2-4 months was correlated with levels of serum leptin in both males and females, and with levels of IGF-I and thyroid hormone in females only. A genome scan showed the presence of polymorphic alleles on chromosomes 2, 6, 7 and 15 with significant effects on body weight at 2-4 months, at 10-12 months, or at both age ranges, showing that weight gain trajectory in this stock is under complex genetic control. Because it provides the earliest known predictor of life span, body weight may be usefully included in screens for induced mutations that alter aging. The evidence that weight in 2-month-old mice is a significant predictor of life span suggests that at least some of the lethal diseases of old age can be timed by factors that influence growth rate in juvenile rodents.     

Resistance of skin fibroblasts to peroxide and UV damage predicts hearing loss in aging mice

Those mice whose skin-derived primary fibroblast cell lines resist lethal injury induced by hydrogen peroxide or UV light show lower age-related decline in hearing. Skin cell lines may provide an easily accessible surrogate index of intrinsic stress resistance that varies among individuals and influences the pace of neurosensory decline in aging mice.     

Nordihydroguaiaretic acid and aspirin increase lifespan of genetically heterogeneous male mice

The National Institute on Aging's Interventions Testing Program was established to evaluate agents that are purported to increase lifespan and delay the appearance of age-related disease in genetically heterogeneous mice. Up to five compounds are added to the study each year and each compound is tested at three test sites (The Jackson Laboratory, University of Michigan, and University of Texas Health Science Center at San Antonio). Mice in the first cohort were exposed to one of four agents: aspirin, nitroflurbiprofen, 4-OH-alpha-phenyl-N-tert-butyl nitrone, or nordihydroguaiaretic acid (NDGA). Sample size was sufficient to detect a 10% difference in lifespan in either sex,with 80% power, using data from two of the three sites. Pooling data from all three sites, a log-rank test showed that both NDGA (p=0.0006) and aspirin (p=0.01) led to increased lifespan of male mice. Comparison of the proportion of live mice at the age of 90% mortality was used as a surrogate for measurement of maximum lifespan;neither NDGA (p=0.12) nor aspirin (p=0.16) had a significant effect in this test. Measures of blood levels of NDGA or aspirin and its salicylic acid metabolite suggest that the observed lack of effects of NDGA or aspirin on life span in females could be related to gender differences in drug disposition or metabolism. Further studies are warranted to find whether NDGA or aspirin, over a range of doses,might prove to postpone death and various age-related outcomes reproducibly in mice.     

A metabolic signature predicts biological age in mice

Our understanding of the mechanisms by which aging is produced is still very limited. Here, we have determined the sera metabolite profile of 117 wild‐type mice of different genetic backgrounds ranging from 8 to 129 weeks of age. This has allowed us to define a robust metabolomic signature and a derived metabolomic score that reliably/accurately predicts the age of wild‐type mice. In the case of telomerase‐deficient mice, which have a shortened lifespan, their metabolomic score predicts older ages than expected. Conversely, in the case of mice that overexpress telomerase, their metabolic score corresponded to younger ages than expected. Importantly, telomerase reactivation late in life by using a TERT‐based gene therapy recently described by us significantly reverted the metabolic profile of old mice to that of younger mice, further confirming an anti‐aging role for telomerase. Thus, the metabolomic signature associated with natural mouse aging accurately predicts aging produced by telomere shortening, suggesting that natural mouse aging is in part produced by presence of short telomeres. These results indicate that the metabolomic signature is associated with the biological age rather than with the chronological age. This constitutes one of the first aging‐associated metabolomic signatures in a mammalian organism.     

Comparative biochemical and stress analysis of genetically selected drosophila strains with different longevities

We have performed a comparative analysis of the effects of age of reproduction on the biochemical (protein, lipid, and glycogen content) and stress resistance (ability to survive starvation, desiccation, and exogenous paraquat) parameters on 10 sister lines of five different Drosophila strains. Four pairs of these sister lines were selected under different regimens for either early or delayed reproduction; the fifth pair was maintained in a nonselected state and served as the baseline strain to which all others were compared. It is generally accepted that the early regimens give rise to short-lived phenotypes, whereas the delayed regimens give rise to long-lived phenotypes. Our results suggest that a mechanism involving lipid and starvation resistance is not operative in our long-lived strains. In addition, a mechanism involving glycogen content and desiccation resistance is only weakly supported. Finally, there is strong support for a mechanism that gives rise to enhanced paraquat resistance and therefore may involve regulatory changes in the pattern of ADS gene expression. In addition, the 15-day early age at reproduction regimen (M type) shows qualitatively similar responses to that of the late age at reproduction regimen (L type). These results suggest that correlations between biochemical traits and longevity must be interpreted with caution. We discuss possible reasons for these results, including the possibility of multiple mechanisms, each leading to a different extended longevity phenotype.     

Lifespan‐extending caloric restriction or mTOR inhibition impair adaptive immunity of old mice by distinct mechanisms

Aging of the world population and a concomitant increase in age‐related diseases and disabilities mandates the search for strategies to increase healthspan, the length of time an individual lives healthy and productively. Due to the age‐related decline of the immune system, infectious diseases remain among the top 5–10 causes of mortality and morbidity in the elderly, and improving immune function during aging remains an important aspect of healthspan extension. Calorie restriction (CR) and more recently rapamycin (rapa) feeding have both been used to extend lifespan in mice. Preciously few studies have actually investigated the impact of each of these interventions upon in vivo immune defense against relevant microbial challenge in old organisms. We tested how rapa and CR each impacted the immune system in adult and old mice. We report that each intervention differentially altered T‐cell development in the thymus, peripheral T‐cell maintenance, T‐cell function and host survival after West Nile virus infection, inducing distinct but deleterious consequences to the aging immune system. We conclude that neither rapa feeding nor CR, in the current form/administration regimen, may be optimal strategies for extending healthy immune function and, with it, lifespan.     

Daumone fed late in life improves survival and reduces hepatic inflammation and fibrosis in mice

The liver is one of the most susceptible organs to aging, and hepatic inflammation and fibrosis increase with age. Chronic inflammation has been proposed as the major molecular mechanism underlying aging and age-related diseases, whereas calorie restriction has been shown to be the most effective in extending mammalian lifespan and to have anti-aging effects through its anti-inflammatory action. Thus, it is necessary to develop effective calorie restriction mimetics. Daumone [(2)-(6R)-(3,5-dihydroxy-6-methyltetrahydropyran-2-yloxy)heptanoic acid], a pheromone secreted by Caenorhabditis elegans, forces them to enter the dauer stage when facing inadequate conditions. Because Caenorhabditis elegans live longer during the dauer stage under energy deprivation, it was hypothesized that daumone may improve survival in mammals by mimicking calorie restriction. Daumone (2 mg kg⁻¹ day⁻¹) was administered orally for 5 months to 24-month-old male C57BL/6J mice. Daumone was found to reduce the risk of death by 48% compared with age-matched control mice, and the increased plasma insulin normally presented in old mice was significantly reduced by daumone. The increased hepatic hypertrophy, senescence-associated β-galactosidase activity, insulin resistance, lipid accumulation, inflammation, oxidative stress, and fibrosis in old mice were significantly attenuated by daumone. From a mechanistic view, daumone reduced the phosphorylation of the IκBα and upregulation of Rela and Nfkbia mRNA in the livers of old mice. The anti-inflammatory effect of daumone was confirmed in lipopolysaccharide-induced liver injury model. Oral administration of daumone improves survival in mice and delivers anti-aging effects to the aged liver by modulating chronic inflammation, indicating that daumone could be developed as an anti-aging compound.     

Prepubertal castration eliminates sex differences in lifespan and growth trajectories in genetically heterogeneous mice

Sex differences in aging and longevity have been widely observed, with females consistently outliving males across human populations. However, the mechanisms driving these disparities remain poorly understood. In this study, we explored the influence of post-pubertal testicular effects on sex differences in aging by prepubertally castrating genetically heterogeneous (UM-HET3) mice, a unique mouse model that emulates human sex differences in age-related mortality. Prepubertal castration eliminated the longevity disparity between sexes by reducing the elevated early- to mid-life mortality rate observed in males and extending their median lifespan to match that of females. Additionally, castration extended the duration of body weight growth and attenuated the inverse correlation between early-age body weight and lifespan in males, aligning their growth trajectories with those of females. Our findings suggest that post-pubertal testicular actions in genetically diverse mice are primarily responsible for sex differences in longevity as well as growth trajectories. These findings offer a foundation for further investigation into the fundamental mechanisms driving sex-specific aging patterns and the development of potential pro-longevity interventions.     

Opposing impacts on healthspan and longevity by limiting dietary selenium in telomere dysfunctional mice

Selenium (Se) is a trace metalloid essential for life, but its nutritional and physiological roles during the aging process remain elusive. While telomere attrition contributes to replicative senescence mainly through persistent DNA damage response, such an aging process is mitigated in mice with inherently long telomeres. Here, weanling third generation telomerase RNA component knockout mice carrying short telomeres were fed a Se‐deficient basal diet or the diet supplemented with 0.15 ppm Se as sodium selenate to be nutritionally sufficient throughout their life. Dietary Se deprivation delayed wound healing and accelerated incidence of osteoporosis, gray hair, alopecia, and cataract, but surprisingly promoted longevity. Plasma microRNA profiling revealed a circulating signature of Se deprivation, and subsequent ontological analyses predicted dominant changes in metabolism. Consistent with this observation, dietary Se deprivation accelerated age‐dependent declines in glucose tolerance, insulin sensitivity, and glucose‐stimulated insulin production in the mice. Moreover, DNA damage and senescence responses were enhanced and Pdx1 and MafA mRNA expression were reduced in pancreas of the Se‐deficient mice. Altogether, these results suggest a novel model of aging with conceptual advances, whereby Se at low levels may be considered a hormetic chemical and decouple healthspan and longevity.     

A dopaminergic gene cluster in the prefrontal cortex predicts performance indicative of general intelligence in genetically heterogeneous mice

Background

Genetically heterogeneous mice express a trait that is qualitatively and psychometrically analogous to general intelligence in humans, and as in humans, this trait co-varies with the processing efficacy of working memory (including its dependence on selective attention). Dopamine signaling in the prefrontal cortex (PFC) has been established to play a critical role in animals'' performance in both working memory and selective attention tasks. Owing to this role of the PFC in the regulation of working memory, here we compared PFC gene expression profiles of 60 genetically diverse CD-1 mice that exhibited a wide range of general learning abilities (i.e., aggregate performance across five diverse learning tasks).

Methodology/Principal Findings

Animals'' general cognitive abilities were first determined based on their aggregate performance across a battery of five diverse learning tasks. With a procedure designed to minimize false positive identifications, analysis of gene expression microarrays (comprised of ≈25,000 genes) identified a small number (<20) of genes that were differentially expressed across animals that exhibited fast and slow aggregate learning abilities. Of these genes, one functional cluster was identified, and this cluster (Darpp-32, Drd1a, and Rgs9) is an established modulator of dopamine signaling. Subsequent quantitative PCR found that expression of these dopaminegic genes plus one vascular gene (Nudt6) were significantly correlated with individual animal''s general cognitive performance.

Conclusions/Significance

These results indicate that D1-mediated dopamine signaling in the PFC, possibly through its modulation of working memory, is predictive of general cognitive abilities. Furthermore, these results provide the first direct evidence of specific molecular pathways that might potentially regulate general intelligence.     

Weekly administration of rapamycin improves survival and biomarkers in obese male mice on high‐fat diet

Recent discoveries have revealed the key role of mTOR (target of rapamycin) in aging. Furthermore, rapamycin extends lifespan in mice, especially in female mice. Here, we treated obese male mice on high‐fat diet with rapamycin given intermittently: either weekly (once a week) or alternating bi‐weekly (three injections every other week). While only marginally reducing obesity, intermittent administration of rapamycin significantly extended lifespan. Significance was achieved for weekly treated group and for the three rapamycin‐received groups combined. In weekly treatment group, 100% mice were alive by the age of 2 years, whereas 60% of mice died in untreated group by this age. The effect of weekly treatment on survival was highly significant and cannot be fully explained by partial reduction in obesity. Alternating bi‐weekly treatments seem to be less effective than weekly treatment, although effects of additional factors (see 3 ) may not be excluded. After one year of treatment, all survived mice were sacrificed 8 days after the last administration of rapamycin to avoid its direct interference with parameters examined. Fasting levels of cardiac and hepatic p‐S6, a marker of mTORC1 activity, were lower in weekly treatment group compared with control mice. In contrast, levels of p‐Akt (S473), glucose, triglycerides and insulin were unchanged, whereas leptin and IGF‐1 tended to be lower. Thus, weekly treatment with rapamycin may slow down aging in obese male mice on high‐fat diet.     

Hematocrit,age, and survival in a wild vertebrate population

Understanding trade‐offs in wild populations is difficult, but important if we are to understand the evolution of life histories and the impact of ecological variables upon them. Markers that reflect physiological state and predict future survival would be of considerable benefit to unraveling such trade‐offs and could provide insight into individual variation in senescence. However, currently used markers often yield inconsistent results. One underutilized measure is hematocrit, the proportion of blood comprising erythrocytes, which relates to the blood's oxygen‐carrying capacity and viscosity, and to individual endurance. Hematocrit has been shown to decline with age in cross‐sectional studies (which may be confounded by selective appearance/disappearance). However, few studies have tested whether hematocrit declines within individuals or whether low hematocrit impacts survival in wild taxa. Using longitudinal data from the Seychelles warbler (Acrocephalus sechellensis), we demonstrated that hematocrit increases with age in young individuals (<1.5 years) but decreases with age in older individuals (1.5–13 years). In breeders, hematocrit was higher in males than females and varied relative to breeding stage. High hematocrit was associated with lower survival in young individuals, but not older individuals. Thus, while we did not find support for hematocrit as a marker of senescence, high hematocrit is indicative of poor condition in younger individuals. Possible explanations are that these individuals were experiencing dehydration and/or high endurance demands prior to capture, which warrants further investigation. Our study demonstrates that hematocrit can be an informative metric for life‐history studies investigating trade‐offs between survival, longevity, and reproduction.     

Female XX sex chromosomes increase survival and extend lifespan in aging mice

Female longevity is observed in humans and much of the animal kingdom, but its causes remain elusive. Using a genetic manipulation that generates XX and XY mice, each with either ovaries or testes, we show that the female XX sex chromosome complement increases survival during aging in male and female mice. In combination with ovaries, it also extends lifespan. Understanding causes of sex‐based differences in aging could lead to new pathways to counter age‐induced decline in both sexes.     

Ultrastructure of testicular macrophages in aging mice

Testicular macrophages of aging mice were studied by TEM. Testicular macrophages retained with Leydig cells the close morphological relationships observed in the adult young animals, but digitations were not found. Lipofuscin granules like those of the Leydig cells from aging mice were observed in the cytoplasm. These organelles were generally absent in the testicular macrophages of young adult mice. Testicular macrophages did not display phagocytosis of the lipofuscin granules. In addition, the latter were not found in the intercellular spaces. These observations indicated that lipofuscin granules were formed, at least in a great part, within testicular macrophages as a consequence of metabolic changes occurring with age. Fine lamellar organization was seen in the lipofuscin granules of both Leydig cells and testicular macrophages. Frequently, lipofuscin granules originated from secondary lysosomes containing lipidic vacuoles only. Together with accumulation of the lipofuscin granules, changes of testicular macrophage fine morphology were observed. Endoplasmic reticulum and Golgi apparatus became poorly developed, and coated vesicles were rarely found. Fewer mitochondria were encountered, but their ultrastructure was not altered. These results suggest that in testicular macrophages lipofuscin accumulation is associated with a functional involution.