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Evidence for lifespan extension and delayed age-related biomarkers in insulin receptor substrate 1 null mice
Colin Selman1, Steven Lingard, Agharul I Choudhury
1Centre for Diabetes and Endocrinology, Department of Medicine, Rayne Institute, University College London, University St., London, UK.
Abstract:
Recent evidence suggests that alterations in insulin/insulin-like growth factor 1 (IGF1) signaling (IIS) can increase mammalian life span. For example, in several mouse mutants, impairment of the growth hormone (GH)/IGF1 axis increases life span and also insulin sensitivity. However, the intracellular signaling route to altered mammalian aging remains unclear. We therefore measured the life span of mice lacking either insulin receptor substrate (IRS) 1 or 2, the major intracellular effectors of the IIS receptors. Our provisional results indicate that female Irs1-/- mice are long-lived. Furthermore, they displayed resistance to a range of age-sensitive markers of aging including skin, bone, immune, and motor dysfunction. These improvements in health were seen despite mild, lifelong insulin resistance. Thus, enhanced insulin sensitivity is not a prerequisite for IIS mutant longevity. Irs1-/- female mice also displayed normal anterior pituitary function, distinguishing them from long-lived somatotrophic axis mutants. In contrast, Irs2-/- mice were short-lived, whereas Irs1+/- and Irs2+/- mice of both sexes showed normal life spans. Our results therefore suggest that IRS1 signaling is an evolutionarily conserved pathway regulating mammalian life span and may be a point of intervention for therapies with the potential to delay age-related processes.
Insights
Altering insulin/IGF1 signaling (IIS) impacts lifespan. Female mice lacking insulin receptor substrate 1 (IRS1) lived longer and showed fewer aging signs, suggesting IRS1 pathway regulates aging.
Area of Science:
- Endocrinology
- Genetics
- Aging Research
Background:
- Alterations in insulin/IGF1 signaling (IIS) are linked to increased mammalian lifespan.
- Impairment of the growth hormone (GH)/IGF1 axis in mouse mutants extends lifespan and improves insulin sensitivity.
- The specific intracellular signaling pathways mediating IIS's effect on aging remain unclear.
Purpose of the Study:
- To investigate the role of insulin receptor substrate (IRS) 1 and IRS2, key intracellular effectors of IIS receptors, in mammalian aging.
- To determine the impact of IRS1 and IRS2 deficiency on lifespan and age-related physiological decline.
Main Methods:
- Measured the lifespan of mice with genetic deficiencies in IRS1 (Irs1-/-) and IRS2 (Irs2-/-).
- Assessed age-sensitive markers of aging, including skin, bone, immune function, and motor performance.
- Evaluated insulin sensitivity and anterior pituitary function in mutant mice.
Main Results:
- Female Irs1-/- mice exhibited significantly increased lifespan and resistance to age-related dysfunction.
- These health improvements in Irs1-/- mice occurred despite mild, lifelong insulin resistance.
- Irs2-/- mice had reduced lifespans, while heterozygous mice (Irs1+/- and Irs2+/-) showed normal lifespans.
- Irs1-/- female mice maintained normal anterior pituitary function.
Conclusions:
- IRS1 signaling is an evolutionarily conserved pathway that regulates mammalian lifespan.
- IRS1 deficiency can extend lifespan and delay aging processes independently of enhanced insulin sensitivity.
- The IRS1 pathway represents a potential therapeutic target for interventions aimed at delaying age-related diseases.
