Early Life Interventions Can Shape Aging

Abstract

It is well documented that the environment of the developing fetus, including availability of nutrients and presence of toxins, can have major impact on adult phenotype, age-related traits and risk of chronic disease. There is also accumulating evidence that postnatal environment can impact adult characteristics related to evolutionary fitness, health, and aging. To determine whether early life hormonal interventions can alter trajectory of aging, we have examined the effects of early life growth hormone (GH) replacement therapy in Prop1^df (Ames dwarf) mice which are GH deficient and remarkably long lived. Twice-daily GH injections between the ages of two and eight weeks completely normalized ("rescued") a number of adult metabolic characteristics believed to contribute to extended longevity of these mutants. Importantly, longevity of Ames dwarf mice was reduced by early life GH treatment. This was associated with histone H3 modifications. We conclude that the trajectory of mammalian aging can be modified by early life interventions. Mechanistic links among interventions during postnatal development, adult metabolic characteristics, aging, and longevity, apparently involve epigenetic phenomena.

Keywords: Developmental Origins of Health and Disease (DOHaD); aging; early life interventions; growth hormone; healthspan; lifespan; mutant mice; postnatal development.

Figure 1

Metabolic alterations in responses to early GH treatment. Various plasma parameters from male Ames dwarf (Prop1^df) and Littermate control male mice (N) subjected to early-life GH treatment. Saline-treated-control mice (black bar), Saline-treated-dwarf mice (white bar), and GH-treated-dwarf mice (grey bar), ^a,b values that do not share a superscript letter are significantly different (p < 0.05). Data represent the means ± SEM (19).

Figure 2

Plasma irisin levels and expression of FNDC5 in muscle tissue of two kinds of slow aging mice, Snell DW, and GHRKO. (A) Irisin content was measured by ELISA on plasma samples of 24-week-old WT and mutant mice (DW, GHRKO, abbreviated GKO). Data are shown as mean ± SEM for each group (n = 6). **P < 0.001 versus WT. (B) Cell lysate was prepared from gastrocnemius muscle of 24-week-old WT and slow aging mice, and protein levels of FNDC5 were measured by western blotting. Representative gel images are shown. (C) Relative protein expression was normalized to β-actin levels. Values are mean ± SEM (n = 4). **P < 0.05 versus WT (38).