Whole-life body composition trajectory and longevity: role of insulin

Abstract

The present study assessed the body composition trajectory of rats (N = 96) placed into 5 groups according to lifespan, using dual-energy x-ray absorptiometry every 6 months until end-of-life. A striking linearity between lifespan and bone mass percentage (not absolute bone mass) was observed. Long-lived rats show a higher bone mass percentage with a delayed insulin rise to a similar peak level as short-lived counterparts, followed by insulin declines and bone mass loss. Decreasing insulin after streptozotocin (STZ) injection caused a rapid bone mass loss (-10.5%) with a decreased 5-day survival rate to 35% in old rats (20 months). Insulin replacement to STZ-injected rats completely blocked bone mass loss and increased the survival rate to 71%. Normal old rats (20 months) had faster lean mass loss despite greater myofiber regeneration (centronucleation) compared with the young rats (4 months). Increased CD68⁺ and CD163⁺ cell infiltration into insulin-depleted muscle suggests a bone marrow cell exhaustion by aging muscle. Bone produces stem cells and phagocytes to continuously rejuvenate peripheral tissues. Our data suggests that aging and unsustainable life is associated with development of disproportionality between bone and the growing body size, partly due to insulin reversal from hyperinsulinemia during late life.

Keywords: cachexia; frailty; longevity; osteopenia; sarcopenia.

Figure 1

Longevity is associated with weight trajectory patterns. Rats (N = 96) ranked into 5 lifespan categories (LS1 to LS5), where all groups of rats show a common trajectory pattern of two discrete life phases: weight gain (long) and weight loss (short) periods (A). An inverse relationship between average survival time and peak weight of the groups ranked from the shortest to the longest lived group (B). Abbreviation: LS, lifespan; LS1 (short-lived, survival time < 579 days); LS2 (survival time 582-672 days); LS3 (survival time 672-738 days); LS4 (survival time 738-870 days); LS5 (long-lived, survival time 870-1032 days).

Figure 2

Development of disparity in muscle, bone, and fat percentage of short-lived and long-lived rats during aging. Long-lived rats (LS4 and LS5) are characterized by relatively higher % bone mass from 6 to 24 months of age (A). Short-lived rats had lowest % muscle mass (B) and highest % fat mass (C) at 6 months of age, whereas long-lived survivors showed progressive declines in % muscle mass and increases in % fat mass with age. Absolute bone mass (D), lean mass (E), and fat mass (F) are shown on the right side. Abbreviation: LS, lifespan; LS1 (short-lived, survival time < 579 days); LS2 (survival time 582-672 days); LS3 (survival time 672-738 days); LS4 (survival time 738-870 days); LS5 (long-lived, survival time 870-1032 days). ¶ Significant difference against long-lived rats (LS5), P < 0.05; * Significant difference against 6^th month, P < 0.05.

Figure 3

Bone mass loss is associated with tumor occurrence and residual survival time after 18 months of age (A). Lower panel shows x-ray images of the top 8 and bottom 8 rats (N = 17) on magnitudes of bone mass loss among rats survived after 18 months (B), demonstrating a severe increased tumorigenesis together with cachexia.

Figure 4

Role of insulin on survival fitness during end-life. Plasma insulin declines (A) from hyperinsulinemic state while glucose (B) remains unchanged from 18-24 months of age. Decreases in survival rate (C) and glycogen storage (D) after insulin loss by streptozotocin injection (S group) is reversed by insulin replacement (SI group, 0.25 IU/kg twice a day) for old rats (20 months of age). Abbreviation: LS, lifespan; LS1 (short-lived, survival time < 579 days); LS2 (survival time 582-672 days); LS3 (survival time 672-738 days); LS4 (survival time 738-870 days); LS5 (long-lived, survival time 870-1032 days). ¶ Significant difference against long-lived rats (LS5), P < 0.05; * Significant difference against 6^th month, P < 0.05; † Significant difference against 18^th month, P < 0.01. ** Significant difference against control group, P < 0.05. Abbreviation: C, vehicle-injected control group; S, Streptozotocin-injected group; SI, Streptozotocin and insulin co-injected group.

Figure 5

Bone marrow derived cell infiltration (CD68⁺ and CD163⁺ cells) in skeletal muscle of old rats altered by insulin. Centrally nucleated fibers (reflecting cell regeneration) (A), cell infiltration (B), CD68⁺ cells (C), and CD163⁺ cells (D) in soleus muscle from young and old rats were measured 5 days after streptozotocin injection (50 mg/kg/ml) and/or insulin injection (0.25 IU/kg twice a day). * Significant difference against C group, P < 0.05; † Significant against Young group, P < 0.05. Abbreviation: C, vehicle-injected control group; S, Streptozotocin-injected group; SI, Streptozotocin and insulin co-injected group.