Life-Span Extension in Mice by Preweaning Food Restriction and by Methionine Restriction in Middle Age

Abstract

Life span can be extended in rodents by restricting food availability (caloric restriction [CR]) or by providing food low in methionine (Meth-R). Here, we show that a period of food restriction limited to the first 20 days of life, via a 50% enlargement of litter size, shows extended median and maximal life span relative to mice from normal sized litters and that a Meth-R diet initiated at 12 months of age also significantly increases longevity. Furthermore, mice exposed to a CR diet show changes in liver messenger RNA patterns, in phosphorylation of Erk, Jnk2, and p38 kinases, and in phosphorylation of mammalian target of rapamycin and its substrate 4EBP1, HE-binding protein 1 that are not observed in liver from age-matched Meth-R mice. These results introduce new protocols that can increase maximal life span and suggest that the spectrum of metabolic changes induced by low-calorie and low-methionine diets may differ in instructive ways.

Differential effects of early-life nutrient restriction in long-lived GHR-KO and normal mice

“…In support of this interpretation, longevity was reduced in GHR-KO females in which a reduction of body weight produced by litter crowding persisted until the age of 2 years and not in males in which body weight difference disappeared during the second half of life. Increased late life mortality of GHR-KO females raised in large litters contrasts sharply with the pronounced beneficial effect of litter crowding on longevity of normal mice studied by Sun et al (Sun et al 2009) and also differs from the somewhat less clear benefit seen in normal females in the present study. We have no explanation for the much smaller longevity benefit of litter crowding in normal animals in the present study in comparison to the mice studied by Sun et al (Sun et al 2009).…”

“…Increased late life mortality of GHR-KO females raised in large litters contrasts sharply with the pronounced beneficial effect of litter crowding on longevity of normal mice studied by Sun et al (Sun et al 2009) and also differs from the somewhat less clear benefit seen in normal females in the present study. We have no explanation for the much smaller longevity benefit of litter crowding in normal animals in the present study in comparison to the mice studied by Sun et al (Sun et al 2009). Differences in the genetic background may have been involved, but recent studies in the Miller laboratory in UM-HET animals (produced by the same crosses as those used by Sun et al) also showed only small and sex-specific extension of longevity in response to litter crowding (data not shown).…”

“…In the current study, litter size was adjusted within the first day of birth by adding pups from another litter or (rarely) by removing pups to produce either Bsmall^(S) litters consisting of eight pups (i.e., the number of pups identical to the size of S litters in the study of Sun et al (Sun et al 2009) or Blarge^(L) litters consisting of 12 pups. The mice set aside for longevity determination were not subjected to any invasive procedures and were undisturbed except for occasional body weight measurements.…”

“…Alterations in nutrient availability during the preweaning period produced by manipulating litter size can also influence adult phenotypic characteristics related to age-related disease and aging (Jennings et al 1999;Martin-Gronert et al 2008). Of particular interest was the report that mild restriction of nutrient availability to suckling pups produced by adding extra pups to a litter (so-called Blitter crowding^) resulted in significant extension of longevity (Sun et al 2009). …”

Growth hormone modulates hypothalamic inflammation in long‐lived pituitary dwarf mice

“…Mice derived from cross‐fostered crowded litters (CL), in which 12 pups are present (‘CL’ mice), are longer lived than mice from cross‐fostered litters of 8 pups, showing that reduced nutrient availability in the first 3 weeks of life can itself lead to extended lifespan (Sun et al ., 2009). Crowded litter mice have lower levels of IGF‐1 at weaning than controls (Sun et al ., 2009), consistent with the idea that low levels of GH and/or IGF‐1 early in life may have long‐lasting benefits for health and longevity. These findings indicate that some important mechanisms of aging are programmed by endocrine signaling during the first few weeks of development.…”