One potential anti-ageing drug that has gathered significant attention is metformin, a medication to help prevent and treat type II diabetes. However, metformin is not the only diabetes drug that may have anti ageing properties.
In a study published in November in the journal Aging Cell, a team led by Elisabetta Mueller, PhD, associate professor in the Department of Medicine at NYU Langone, identified a promising set of candidates for further investigation: thiazolidinediones such as rosiglitazone and pioglitazone, commonly used to treat type 2 diabetes. These drugs increase insulin sensitivity by targeting a nuclear receptor known as PPARγ (peroxisome proliferator activated receptor gamma).
When activated, PPARγ binds to specific regions of the DNA and can either increase or decrease the expression of genes. PPARγ is a key regulator of adipogenesis (the formation of fat cells). In older age, activation of PPARγ appears to favour the production of brown fat (which consumes fat to generate heat) to the detriment of white fat (which acts primarily as a fat store). PPARγ activation also has various other metabolic benefits including improved blood sugar control.
Previous studies by Dr. Mueller and others have shown that PPARγ ligands have anti-inflammatory, anti-cancer, and neuroprotective effects, and that modulation of PPARγ levels in mice impacts lifespan. These findings led Dr. Mueller to theorize that thiazolidinediones—which function as PPARγ agonists—could be useful as anti-aging agents.
Researchers studied the effects of one of these PPARγ-targeting drugs, rosiglitazone, in ageing mice. In human subjects, rosiglitazone has been associated with an increased risk of bone fractures and myocardial infarctions. To see if the theorised benefits of activating PPARγ could be achieved while minimising these side effects, researchers gave mice a dose of rosiglitazone far below what has previously been used in animal models.
Tests for adverse effects showed no significant differences in water retention, cardiac function, or bone density in treated versus untreated animals. Indeed, median lifespan in the treated mice was extended by 11 percent—from 777 to 864 days.
Analysis in isolated cells demonstrated that treatment was associated with increased glucose uptake in adipocytes […]. Furthermore, analysis of gene expression […] revealed molecular changes consistent with increased browning. These data suggest that low doses of rosiglitazone can effectively improve insulin sensitivity, one of the hallmarks of metabolic aging, and are sufficient to induce fat cells to burn energy rather than store it.
Researchers also noted behavioural changes:
Behavioural studies revealed decreased anxiety-like symptoms and improved cognitive function in the treated mice.
A long-term study is needed to identify for certain whether any of these benefits will translate to humans. However, researchers decided to search for indications of human benefits of thiazolidinediones in existing medical data. To do this, they conducted a retrospective analysis of around 250 000 patients who were prescribed pioglitazone (a similar drug to rosiglitazone) or glimepiride (a drug that increases insulin secretion, but doesn’t have any effect on PPARγ).
In the pioglitazone group, 50 percent of patients survived for at least 12 years; in the glimepiride group, the survival curve dipped below 50 percent after only 10 years.
Of course, this could simply mean that glimepiride is prescribed more frequently to less healthy patients, or is simply a less effective drug overall, rather than being due to lifespan extending properties of pioglitazone. Nevertheless, these results are at least consistent with the theorised benefits of PPARγ activation, and warrant further investigation.
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