GDF11 as a Calorie Restriction Mimetic

GDF11 was one of the first factors in blood identified as a possible explanation for the outcome of heterochronic parabiosis. When a young and old mouse have their circulatory systems joined, some aspects of aging reverse in the old mouse, and some aspects of aging are accelerated in the young mouse. GDF11 levels decline with age, and it was thought that increased levels of GDF11 provided by the young animal could act to improve function of cells and tissues in the older animal - though it was not well understood as to how GDF11 worked to produce these results.

Since then there has been some debate over whether or not the original GDF11 research was technically correct, as well as some debate over whether or not factors in young blood are in fact responsible for parabiosis effects. Researchers have demonstrated benefits in old mice by delivery of GDF11 as a treatment, however. A company, Elevian, was founded to carry forward the development of GDF11 as basis for clinical therapy.

Meanwhile, research into GDF11 and aging continues elsewhere in the scientific community. Today's very interesting open access research provides evidence for GDF11 to produce benefits in large part through triggering many of the same mechanisms as calorie restriction. If this is the primary mechanism of action, it would make GDF11 much less interesting as a basis for human therapy. Firstly because calorie restriction already exists, and is essentially free, and secondly because the practice of calorie restriction produces much larger effects on life span in short-lived species than it does in long-lived species.

A blood factor involved in weight loss and aging

In a previous study using mouse models, scientists observed that injecting aged mice with blood from young mice rejuvenated blood vessels in the brain, and consequently improved cerebral blood flow, while increasing neurogenesis and cognition. Scientists put forward the theory that, since calorie restriction and supplementation with young blood were effective in rejuvenating organs, they most likely have certain mechanisms in common.

They therefore examined the molecule GDF11, which belongs to the GDF (Growth Differentiation Factor) protein family and is involved in embryonic development. GDF11 was already known to scientists for its ability to rejuvenate the aged brain. By injecting this molecule into aged mouse models, researchers noticed an increase in neurogenesis and blood vessel remodeling. The scientists also observed that the mice administered with GDF11 had lost weight without changing their appetite. This observation led them to believe that GDF11 could be a link between calorie restriction and the regenerating effects of young blood.

The next step was to confirm this theory by studying adiponectin, a hormone secreted by adipose tissue which induces weight loss without affecting appetite. In animals that have undergone calorie restriction, the blood levels of this hormone are high. In animals that were administered GDF11, researchers also observed high levels of adiponectin, and this shows that GDF11 causes metabolic changes similar to those induced by calorie restriction. Until recently, there has been controversy over the role of GDF11 in aging, and its mechanisms were largely unknown. The findings of this study show that by inducing phenomena similar to those reported for calorie restriction leading to the stimulation of adiponectin and neurogenesis, GDF11 contributes to the birth of new neurons in the brain.

Systemic GDF11 stimulates the secretion of adiponectin and induces a calorie restriction-like phenotype in aged mice

Here, we present evidence that GDF11 induces a healthy calorie restriction-like phenotype together with brain rejuvenation in aged mice, and it acts by stimulating the secretion of adiponectin directly on adipocytes. We demonstrate a potent role for GDF11 as a metabolic actor in the aged organism based on the following findings: (a) systemic administration of GDF11 induced healthy weight loss as early as 1 week after treatment, (b) this weight loss reached a plateau throughout the rest of the treatment and was maintained for 3 weeks beyond the end of the treatment, (c) GDF11 levels were increased in aged mice that were subjected to calorie restriction, (d) metabolic changes were independent of GDF15 activation or anorexia, but correlated with changes in adiponectin levels and the insulin/IGF-1 metabolic pathway, (e) GDF11 activated adiponectin secretion directly from adipocytes, and (f) all the above changes correlated with a brain rejuvenation phenotype in aged mice.

Comments

@Reason, others: Does that mean there will be developed a pill Tham mimics CR so we can extend our lives 2-5 years without going hungry?

Posted by: thomas.a at November 7th, 2019 3:52 AM

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