Early life growth hormone treatment shortens longevity and decreases cellular stress resistance in long-lived mutant mice

Abstract

Hypopituitary Ames dwarf mice were injected either with growth hormone (GH) or thyroxine for a 6-wk period to see whether this intervention would reverse their long life span or the resistance of their cells to lethal stresses. Ames dwarf mice survived 987 ± 24 d (median), longer than nonmutant control mice (664 ± 48), but GH-injected dwarf mice did not differ from controls (707 ± 9). Fibroblast cells from Ames dwarf mice were more resistant to cadmium than cells from nonmutant controls (LD(50) values of 9.98 ± 1.7 and 3.9 ± 0.8, respectively), but GH injections into Ames dwarf mice restored the normal level of cadmium resistance (LD(50)=5.8 ± 0.9). Similar restoration of normal resistance was observed for fibroblasts exposed to paraquat, methyl methanesulfonate, and rotenone (P<0.05 in each case for contrast of GH-treated vs. untreated dwarf mice; P<0.05 for dwarf vs. nonmutant control mice.) T4 injections into Ames dwarf mice, in contrast, did not restore normal life span. We conclude that the remarkable life-span extension of Ames dwarf mice, and the stress resistance of cells from these mice, depends on low levels of GH exposure in juvenile and very young adult mice.

Figure 1.

Kaplan–Meier survival plot of Ames dwarf mice treated with bGH [dwarf (GH)], untreated WT controls, and untreated Ames dwarf mice [dwarf (saline)] (n=9–10). All mice were males treated 2×/d for 6 wk starting at age 2 wk via s.c. injection (6 μg/g bw/d).

Figure 2.

Body weight of Ames dwarf and control WT male mice subjected to 6 wk of GH treatment. Ames dwarf (df) mice were exposed between 2 and 8 wk of age (as indicated) with bGH (df/df-bGH treated, n =22). Untreated WT (n=9) and df/df (n=17) were used as controls. Time points represent mean ± se weight of each group.

Figure 3.

Results of GTTs in GH-treated Ames dwarf (df/df-bGH treated) and untreated WT and df/df mice. All groups were deprived of food overnight. In the morning, mice were injected i.p. with glucose (2 g/kg bw). Glucose was measured in samples collected from the tail vein at specified time points. Values are means ± se. A) GTT 1 d after last GH injection. B) GTT 1 mo after last GH injection.

Figure 4.

Kaplan–Meier survival plot of male and female Ames dwarf mice treated with T4 or saline (n=10–11). All mice were treated for 6 wk at the age of 2–8 wk.

Figure 5.

Body weight of male and female Ames dwarf mice subjected to 6 wk of treatment with T4 or saline (n=10–11) during the period indicated on the graph. Time points represent means ± se.

Figure 6.

Stress resistance in skin-derived fibroblasts from dwarf mice treated with pGH, untreated WT controls, and df/df male mice. Symbols represent individual mice of the indicated genotype; horizontal rule indicates mean value in each case; n=11–4. ^a,bValues that do not share a superscript letter are statistically significant (P<0.05).