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 Prop1df (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.
Highlights
Life Interventions Impact Aging experiencing periods of severe food deprivation [4–6] and in experimental animals, primarily sheep and rats subjected to calorie or protein restriction during pregnancy [7–9], firmly established the concept of Developmental Origins of Health and Disease (DOHaD)
The mechanisms of early life events on adult functioning and disease risk encompassed in the concept of DOHaD are unlikely to include changes in the DNA sequence or integrity, and have been linked to epigenetic effects, primarily changes in the methylation and/or acetylation of DNA and chromosomal proteins leading to alterations in gene expression [15, 16]
Subsequent collaborative studies identified other adult characteristics related to mechanisms of aging that were substantially altered in Ames dwarf mice and largely or completely normalized by six weeks of treatment with growth hormone (GH) in early life
Summary
Developmental Origins of Health and DiseaseImpact of early life events on the characteristics of an adult organism is a concept which is well established in developmental biology. Studies dating back to the middle of the last century documented the potential of environmental changes during development to produce alterations in adult phenotype that mimic the effects of genetic mutations, the so-called “phenocopies.” Early interpretation of experimental evidence in this field, including proposal of the concept of canalization of development [1], represent classical milestones in the history of developmental biology.
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