Genetics of life span in mice

Thymic involution that occurs earlier in some individuals than others may be the result of complex interactions between genetic factors and the environment. Such interactions may produce defects of thymus-dependent immune regulation associated with susceptibility to developing autoimmune diseases, malignancy, and an increased number of infections associated with aging.The major histocompatibility complex may be important in determining profiles of cause of death and length of life in mice. Genetic influences on life span involve interactions between loci and allelic interactions during life which may change following viral infections or exposure to other environmental factors. We have used different experimental protocols to study the influence of H-2 on life span and found that interactions between genetic regions, are inconsistent, particularly when comparing mice infected or not infected with Sendai virus.Genes important for life span need to be studied against many genetic backgrounds and under differing environmental conditions because of the complexity of the genetics of life span. Several genetic models were used to demonstrate that the MHC is a marker of life span in backcross and intercross male mice of the H-2^d and H-2^b genotypes in B10 congenic mice. Females lived longer than males in backcross and intercross mice, while males lived longer than females in B10 congenics. H-2^d was at a disadvantage for life span in backcross mice of the dilute brown and brown males exposed to Sendai infection, but intercross mice not exposed to Sendai virus of the same genotype were not at a disadvantage. H-2^d mice were not disadvantaged when compared to H-2^b in B10 congenics that had not been exposed to Sendai virus infection but the reverse was true when they were exposed. Overall, all our studies suggest that genetic influences in life span may involve interactions between loci and many allelic interactions in growing animals or humans. These genetic influences on life span may vary after they are exposed to infections or other environmental conditions. This paper emphasizes the need to use several genetic models, especially animals that have been monitored for infections, to study the genetics of life span.     

Leaf life span of floating-leaved plants

Photosynthetic capacity of floating-leaved plants is relatively high comparable with terrestrial herbaceous plants, though floating-leaved plants have a much smaller biomass with a leaf area index seldom exceeding 2m²m^-2. Their rather small biomass accumulation is related to higher turnover of leaf biomass or shorter leaf life span. Life span of floating leaves reported in the literature ranged mostly from 13 to 35 days, shorter than that of any other groups of herbaceous macrophytes. Floating-leaved plants are known to show considerably high plasticity in their leaf form. Leaf life span could be prolonged for Nymphoides peltata (Gmel.) O. Kuntze grown in a terrestrial environment and for emergent leaves of Nelumbo nucifera Gaertn. Their short leaf life span seems to be closely related to the fact that old leaves covered by newly formed ones are inevitably compelled to be submerged and lose their function as a photosynthetic apparatus.Abbreviations LAI leaf area index - PFD photosynthetic photon flux density     

Antagonizing Methuselah to extend life span

A recent report describes the identification through the use of in vitro selection of a peptide that antagonizes Methuselah signaling in Drosophila in vitro and extends fly life span in vivo.     

Alternative mitochondrial fuel extends life span

In this issue of Cell Metabolism, Ristow and colleagues (Zarse et?al., 2012) elucidate a conserved mechanism through which reduced insulin-IGF1 signaling activates an AMP-kinase-driven metabolic shift toward oxidative proline metabolism. This, in turn, produces an adaptive mitochondrial ROS signal that extends worm life span. These findings further bolster the concept of mitohormesis as a critical component of conserved aging and longevity pathways.     

Post-reproductive life span and demographic stability

Recent field studies suggest that it is common in nature for animals to outlive their reproductive viability. Post-reproductive life span has been observed in a broad range of vertebrate and invertebrate species. But post-reproductive life span poses a paradox for traditional theories of life history evolution. The commonly cited explanation is the “grandmother hypothesis”, which applies only to higher, social mammals. We propose that post-reproductive life span evolves to stabilize predator-prey population dynamics, avoiding local extinctions. In the absence of senescence, juveniles would be the most susceptible age class. If juveniles are the first to disappear when predation pressure is high, this amplifies the population’s risk of extinction. A class of older, senescent individuals can help shield the juveniles from predation, stabilizing demographics and avoiding extinction. If, in addition, the life history is arranged so that the older individuals are no longer fertile, the stabilizing effect is further enhanced.     

Liver-derived IGF-I regulates mean life span in mice

Background

Transgenic mice with low levels of global insulin-like growth factor-I (IGF-I) throughout their life span, including pre- and postnatal development, have increased longevity. This study investigated whether specific deficiency of liver-derived, endocrine IGF-I is of importance for life span.

Methods and Findings

Serum IGF-I was reduced by approximately 80% in mice with adult, liver-specific IGF-I inactivation (LI-IGF-I^-/- mice), and body weight decreased due to reduced body fat. The mean life span of LI-IGF-I^-/- mice (n = 84) increased 10% vs. control mice (n = 137) (Cox''s test, p<0.01), mainly due to increased life span (16%) of female mice [LI-IGF-I^-/- mice (n = 31): 26.7±1.1 vs. control (n = 67): 23.0±0.7 months, p<0.001]. Male LI-IGF-I^-/- mice showed only a tendency for increased longevity (p = 0.10). Energy expenditure, measured as oxygen consumption during and after submaximal exercise, was increased in the LI-IGF-I^-/- mice. Moreover, microarray and RT-PCR analyses showed consistent regulation of three genes (heat shock protein 1A and 1B and connective tissue growth factor) in several body organs in the LI-IGF-I^-/- mice.

Conclusions

Adult inactivation of liver-derived, endocrine IGF-I resulted in moderately increased mean life span. Body weight and body fat decreased in LI-IGF-I^-/- mice, possibly due to increased energy expenditure during exercise. Genes earlier reported to modulate stress response and collagen aging showed consistent regulation, providing mechanisms that could underlie the increased mean life span in the LI-IGF-I^-/- mice.     

7-Hydroxydehydroepiandrosterone epimers in the life span.

Evidence has been accumulated that 7-hydroxyepimers of dehydroepiandrosterone (7-OH-DHEA), may act as locally active immunomodulatory and immunoprotective agents, counteracting exaggerated actions of glucocorticoids. Since Skinner et al. (1977) developed the first unspecific RIA, it has been known that 7alpha-OH-DHEA is present in near nanomolar concentration in human blood. No data have been available, however, on its changes during the human life. Using recently developed specific radioimmunoassays for determination of both 7-OH-DHEA epimers, 7alpha- and 7beta-OH-DHEA were measured in sera from 252 males and 172 females, representing age groups from 10 to 91 years (males) and from 10 to 72 years (females). The dependence of 7-OH-DHEA levels on age was evaluated by using polynomial fitting of the 4th or 5th degree. In contrast to men, where a distinct decline with age occurred, two local maxima have been recorded round the age 22 and 53, respectively, in females. The curves of age dependence of 7-OH-DHEA levels in both sexes resembled those of previously determined unconjugated DHEA, but in the latter case the second maximum in women was found about 10 years earlier than 7-OH-DHEA, in a premenopausal period. The levels of both 7-OH-DHEA epimers correlated excellently with each other.     

Regulation of the life span in unicellular eukaryotes

The review considers the mechanisms of nucleic and mitochondrial control of the life span of unicellular eukaryotes. Special attention is given to analysis of the mechanisms of functioning of telomerase complex, the mechanisms of varied expression of the genes regulating the cell cycle, and the mitochondrial retrograde pathway.     

Prenatal alcohol exposure shortens life span in rats

In a study of the effects of in utero alcohol exposure on life span in rats, pregnant rats were intubated twice daily with 3.5 gm/kg alcohol on gestational days 11-21 or with an isocaloric sucrose solution. These latter animals were pair-fed and pair-watered to alcohol-treated animals. A third group served as nontreated ad lib-fed controls. At birth, all offspring were removed from their biological mothers, culled to eight per litter, and placed with nontreated surrogate dams. Alcohol-exposed animals died at a significantly younger age than pair-fed and ad lib controls and never attained the same maximum body weights as control animals. For females prenatally exposed to alcohol, life span was shortened by about 20 weeks; in male cohorts, life span was shortened by about 2.5-7 weeks.     

Plasmid accumulation reduces life span in Saccharomyces cerevisiae

Aging in the yeast Saccharomyces cerevisiae is under the control of multiple pathways. The production and accumulation of extrachromosomal rDNA circles (ERCs) is one pathway that has been proposed to bring about aging in yeast. To test this proposal, we have developed a plasmid-based model system to study the role of DNA episomes in reduction of yeast life span. Recombinant plasmids containing different replication origins, cis-acting partitioning elements, and selectable marker genes were constructed and analyzed for their effects on yeast replicative life span. Plasmids containing the ARS1 replication origin reduce life span to the greatest extent of the plasmids analyzed. This reduction in life span is partially suppressed by a CEN4 centromeric element on ARS1 plasmids. Plasmids containing a replication origin from the endogenous yeast 2 mu circle also reduce life span, but to a lesser extent than ARS1 plasmids. Consistent with this, ARS1 and 2 mu origin plasmids accumulate in approximately 7-generation-old cells, but ARS1/CEN4 plasmids do not. Importantly, ARS1 plasmids accumulate to higher levels in old cells than 2 mu origin plasmids, suggesting a correlation between plasmid accumulation and life span reduction. Reduction in life span is neither an indirect effect of increased ERC levels nor the result of stochastic cessation of growth. The presence of a fully functional 9.1-kb rDNA repeat on plasmids is not required for, and does not augment, reduction in life span. These findings support the view that accumulation of DNA episomes, including episomes such as ERCs, cause cell senescence in yeast.     

Cellular life span and the Warburg effect

Enhanced glycolysis is observed in most of cancerous cells and tissues, called as the Warburg effect. Recent advance in senescent biology implicates that the metabolic shift to enhanced glycolysis would be involved in the early stage during multi-step tumorigenesis in vivo. Enhanced glycolysis is essential both in the step of immortalization and transformation, as it renders cells resistant to oxidative stress and adaptive to hypoxic condition, respectively. ES, immortalized primary, and cancerous cells display the common concerted metabolic shift, including enhanced glycolysis with reduced mitochondrial respiration by poorly characterized mechanism. Discovery of a novel regulatory mechanism for such a metabolic shift might be essential for the future development of cancer diagnosis and anti-cancer therapy.