The exceptional longevity of Ames dwarf (DF) mice can be abrogated by a brief course of growth hormone (GH) injections started at 2 weeks of age. This transient GH exposure also prevents the increase in cellular stress resistance and decline in hypothalamic inflammation characteristic of DF mice. Here, we show that transient early‐life GH treatment leads to permanent alteration of pertinent changes in adipocytes, fat‐associated macrophages, liver, muscle, and brain that are seen in DF mice. Ames DF mice, like Snell dwarf and GHRKO mice, show elevation of glycosylphosphatidylinositol specific phospholipase D1 in liver, neurogenesis in brain as indicated by BDNF and DCX proteins, muscle production of fibronectin type III domain‐containing protein 5 (a precursor of irisin), uncoupling protein 1 as an index of thermogenic capacity in brown and white fat, and increase in fat‐associated anti‐inflammatory macrophages. In each case, transient exposure to GH early in life reverts the DF mice to the levels of each protein seen in littermate control animals, in animals evaluated at 15–18 months of age. Thus, many of the traits seen in long‐lived mutant mice, pertinent to age‐related changes in inflammation, neurogenesis, and metabolic control, are permanently set by early‐life GH levels.

Glycosylphosphatidylinositol‐specific phospholipase D1 (GPLD1) hydrolyzes inositol phosphate linkages in proteins anchored to the cell membrane. Mice overexpressing GPLD1 show enhanced neurogenesis and cognition. Snell dwarf (DW) and growth hormone receptor knockout (GKO) mice show delays in age‐dependent cognitive decline. We hypothesized that augmented GPLD1 might contribute to retained cognitive function in these mice. We report that DW and GKO show higher GPLD1 levels in the liver and plasma. These mice also have elevated levels of hippocampal brain‐derived neurotrophic factor (BDNF) and of doublecortin (DCX), suggesting a mechanism for maintenance of cognitive function at older ages. GPLD1 was not increased in the hippocampus of DW or GKO mice, suggesting that plasma GPLD1 increases elevated these brain proteins. Alteration of the liver and plasma GPLD1 was unaltered in mice with liver‐specific GHR deletion, suggesting that the GH effect was not intrinsic to the liver. GPLD1 was also induced by caloric restriction and by each of four drugs that extend lifespan. The proteome of DW and GKO mice is molded by selective translation of mRNAs, involving cap‐independent translation (CIT) of mRNAs marked by N6 methyladenosine. Because GPLD1 protein increases were independent of the mRNA level, we tested the idea that GPLD1 might be regulated by CIT. 4EGI‐1, which enhances CIT, increased GPLD1 protein without changes in GPLD1 mRNA in cultured fibroblasts and mice. Furthermore, transgenic overexpression of YTHDF1, which promotes CIT by reading m6A signals, also led to increased GPLD1 protein, showing that elevation of GPLD1 reflects selective mRNA translation.

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