• Log in with Facebook Log in with Twitter Log In with Google      Sign In    
  • Create Account
  LongeCity
              Advocacy & Research for Unlimited Lifespans

Photo

Reduced Insulin Modestly Extends Life in Mice


  • Please log in to reply
No replies to this topic

#1 reason

  • Guardian Reason
  • 1,101 posts
  • 241
  • Location:US

Posted 14 July 2017 - 12:32 PM


Researchers here demonstrate that reducing the levels of circulating insulin in mice extends life by 10% or so in the best scenario they tested. Insulin, insulin-like growth factor 1 (IGF-1), and growth hormone are all closely linked in their interactions, a well-studied area of metabolism that is connected to the pace of aging through its influence on most of the fundamental activities of cells. Adjusting metabolism to slow aging isn't a promising path forward, however. We can already see the likely bounds of the possible in the known effects of exercise, diet, and calorie restriction, as well as in some human lineages with similar loss of function mutations to those created in long-lived genetically engineered mouse lineages. Slowing down the accumulation of cell and tissue damage can only modestly slow aging. If we want more than that, we must look instead to therapies that repair and reverse this damage so as to produce rejuvenation.

As insulin and Igf1 share nearly identical downstream signaling pathways in mammals, and act in part via hybrid insulin/Igf1 heterodimer receptors that can bind to either ligand, the relative functions of these two ligands have not been completely delineated. Many studies have focused on Igf1 as the primary ligand which mediates the lifespan-altering effects through this signaling cascade in mammals, but the impact of directly altering insulin levels on longevity had not been evaluated.

Insulin resistance is a common feature of mammalian aging and a risk factor for numerous age-related diseases. Although this suggests that reducing insulin signaling could be detrimental for mammalian healthspan, it is important to consider that conventionally defined insulin resistance (i.e., impaired insulin-stimulated glucose disposal) is not a generalized reduction of all insulin signaling. Instead, some insulin-regulated processes are maintained at normal capacity in the "insulin resistant" state, while others are downregulated. Moreover, circulating levels of the insulin ligand are elevated with insulin resistance. The commonly accepted paradigm posits that insulin levels rise as a compensatory response to prevent hyperglycemia when there is insufficient insulin-stimulated glucose uptake. However, causality between the closely associated conditions of systemic insulin resistance and insulin hypersecretion has remained controversial, and it has been suggested that hyperinsulinemia could be an early, primary cause of insulin resistance, obesity, and eventually type 2 diabetes. Genetic loss-of-function experiments targeting insulin itself present an ideal opportunity to disentangle hyperinsulinemia from insulin resistance and to evaluate the lifelong effects of limiting endogenous insulin production and secretion.

To determine how moderately lowering the insulin ligand would affect late-life glucose homeostasis and longevity in mammals, we compared mice with either full or partial expression of the ancestral insulin gene Ins2. Since altering insulin gene dosage does not affect circulating insulin levels in all contexts, we used a mouse model in which the rodent-specific insulin gene (Ins1) was fully inactivated to prevent compensatory Ins1 expression. We designed our experiment to evaluate these animals in the context of two distinct diets (diet A: moderate-energy diet; diet B: high-energy diet). Remarkably, we found that across both diets, mice with reduced circulating insulin levels had improved insulin sensitivity with advanced age and exhibited lifespan extension without changing Igf1 levels. These results suggest a causal contribution for hyperinsulinemia in age-dependent insulin resistance and point to the modest suppression of insulin as a safe and attainable strategy for extending lifespan.

Link: http://dx.doi.org/10...rep.2017.06.048


View the full article at FightAging
  • Ill informed x 1




1 user(s) are reading this topic

0 members, 1 guests, 0 anonymous users