IGF-1 has sexually dimorphic, pleiotropic, and time-dependent effects on healthspan, pathology, and lifespan

Abstract

Reduced circulating levels of IGF-1 have been proposed as a conserved anti-aging mechanism that contributes to increased lifespan in diverse experimental models. However, IGF-1 has also been shown to be essential for normal development and the maintenance of tissue function late into the lifespan. These disparate findings suggest that IGF-1 may be a pleiotropic modulator of health and aging, as reductions in IGF-1 may be beneficial for one aspect of aging, but detrimental for another. We postulated that the effects of IGF-1 on tissue health and function in advanced age are dependent on the tissue, the sex of the animal, and the age at which IGF-1 is manipulated. In this study, we examined how alterations in IGF-1 levels at multiple stages of development and aging influence overall lifespan, healthspan, and pathology. Specifically, we investigated the effects of perinatal, post-pubertal, and late-adult onset IGF-1 deficiency using genetic and viral approaches in both male and female igf ^f/f C57Bl/6 mice. Our results support the concept that IGF-1 levels early during lifespan establish the conditions necessary for subsequent healthspan and pathological changes that contribute to aging. Nevertheless, these changes are specific for each sex and tissue. Importantly, late-life IGF-1 deficiency (a time point relevant for human studies) reduces cancer risk but does not increase lifespan. Overall, our results indicate that the levels of IGF-1 during development influence late-life pathology, suggesting that IGF-1 is a developmental driver of healthspan, pathology, and lifespan.

Keywords: Aging; Cancer; Insulin-like growth factor-1; Longevity; Pathology; Somatomedin C.

Fig. 1

Inducing IGF-1 deficiency at distinct time periods of life. a Model of circulating IGF-1 levels throughout mouse life in the various treatment groups (LID_10d, LID_5m, LID_15m). The black dotted line represents the average human concentrations of IGF-1 throughout the lifespan (scaled to match our study in mice). Average circulating IGF-1 levels were assessed with an ELISA at multiple time points in male (b) and female (c) mice. The solid bar indicates levels at 4–5 months of age, slanted bars indicate 12–15 months of age, and checkered bars indicate 24–25 months of age. The asterisk indicates significant difference from the 4–5-month blood levels while the pound sign indicates a significant difference from control (WT) mice at that age (n = 37–43 in the treatment groups, 113 male controls, and 123 female controls) (p < 0.05). d, e IGF-1 mRNA expression was assessed in the liver (left panels) and brain (right panels) of male (d) and female (e) mice at 25–27 months of age (n = 6–10). Body weight (f), fat mass normalized to body weight (g), and lean mass normalized to body weight (h) was measured in male mice at multiple time points in life. Body weight (f), fat mass normalized to body weight (g), and lean mass normalized to body weight (h) was measured in female mice at multiple time points in life. In panels d–k, the asterisk indicates significant difference compared to WT control (n = 37–43 in the treatment groups, 113 male controls, and 123 female controls) (p < 0.05)

Fig. 2

IGF-1 deficiency did not increase healthspan at 25–27 months of age. Average circulating levels of IGF-1 (a), growth hormone (b), and adiponectin (c) in male (left panels) and female (right panels) mice were quantified using ELISAs (n = 12–18 per treatment group, 34–51 for controls). d Base of support and average duty cycle (E, % utilization of each foot) in males (left panels) and females (right panels) was assessed using the CatWalk (n = 13–17 per treatment group, 34–51 for controls). Average grip strength over three trials was assessed using a horizontal force meter at 25–27 months of age in male (left panel) and female (right panel) mice (n = 12–18 per treatment group, 34–51 for controls). Learning and memory was assessed in a subset of male mice using the Barnes Maze. Average path length to the escape box was quantified over 4 days (three trials per day) (n = 8–15 per group). The asterisks indicate a significant difference compared to control animals (p < 0.05)

Fig. 3

IGF-1 deficiency beginning earlier in life extends female lifespan. a Survival curve analysis of 121 control (black), 39 LID_10d (red), 44 LID_5m (green), and 38 LID_15m (blue) male mice. Lifespan extension was assessed using the average median lifespan (b) and the average maximal lifespan (c, remaining 10% survival) of male mice in the various treatment groups. d Survival curves of 130 control (black), 38 LID_10d (red), 43 LID_5m (green), and 45 LID_15m (blue) female mice. Lifespan extension was assessed using the average median lifespan (e) and the average maximal lifespan (f, remaining 10% survival) of female mice in the various treatment groups. The age of cancer-induced mortality (relative to total cancer-induced deaths) was plotted for male (g) and female (h) mice. Sixty-three percent of all deaths were induced by cancer. The asterisks indicate a significant difference compared to control animals (p < 0.05)

Fig. 4

IGF-1 deficiency influences disease and cancer burden at the end of life. The average number of organs per animal with pathology (a), number of diseases per animal (b), and number of cancer types per animal (c) in male mice, as assessed with histological pathology. Average number of organs per animal with disease (d), number of diseases per animal (e), and number of cancer types per animal (f) in female mice. The asterisk indicates significant difference compared to control animals (p < 0.05)

Fig. 5

Tissue-specific pathology associated with IGF-1 deficiency. The percent mice with glomerular nephritis (left panels) and the average grade of nephritis (right panels) at the end of life in male (a) and female (b) mice. The percent mice with hepatocellular carcinoma in males (c) and females (d), as assessed with histological pathology. The percent mice with lordokyphosis in males (e) and females (f). The asterisk indicates significant difference as assessed using chi-squared analysis