Photo: Ed Reschke/Getty
Aging leads to a multitude of disorders caused by cellular senescence, tissue damage, and organ dysfunction. In 2020, a preclinical and retrospective study by researchers at ٺƵ Health showed that a type of medication long used to increase insulin sensitivity can prevent or delay many age-related pathologies—potentially increasing both health span and longevity.
Targeting a Key Receptor
In recent years, studies have reported that, in addition to a balanced diet and physical activity, certain pharmacological treatments—targeting chronic inflammation, insulin sensitivity, or mitochondrial activity—may help to slow the aging process. Ongoing research seeks to develop anti-aging drugs by targeting these pathways, and to determine whether existing medications for various disorders might incidentally have anti-aging properties.
In a , a team led by , associate professor in the at ٺƵ, 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).
Dr. Mueller is an expert in adipose tissue biology and the role fat cells play in obesity, aging, and metabolic disease. In a , she and her colleagues reported that PPARγ, a key regulator of adipogenesis, shifts function with age. Compared with controls, middle-aged mice with ablation of PPARγ in subcutaneous fat tissue had more white fat composed of larger adipocytes, increased insulin resistance, decreased thermogenesis, reduced levels of brown fat genes, and disadvantageous changes to several other metabolic indicators. In younger mice, in contrast, PPARγ ablation caused a decrease in the amount of fat associated with a lipoatrophic phenotype.
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.
Low Doses in Mice Provide Significant Benefits
The new study was the first to evaluate the long-term impact of rosiglitazone in mice without predisposing genetic alterations, as well as the first to examine the broad range of mechanisms by which the drug exerts its effects. Dr. Mueller’s team began with 14-month-old male mice (middle-age mice), administering the medication over the course of their remaining lifespan and assessed the effects at 3 and 6 months after initiation of the treatment.
Because rosiglitazone at standard doses has been associated with elevated risk of water retention, myocardial infarction, and bone fractures in human subjects, the researchers used an oral dose of 1 mg/kg of weight per day—a fraction of the dosages previously used in animal models. “We wanted to see if we could squeeze out the benefits of activating the PPARγ pathway while diminishing side effects as much as possible,” Dr. Mueller explains.
The results were striking. At the end of the treatment period, mice given rosiglitazone showed improved insulin sensitivity compared with controls. Treated mice maintained a stable body weight over time, while control mice displayed age-related loss of body weight and fat tissue. Behavioral studies revealed decreased anxiety-like symptoms and improved cognitive function in the treated mice.
Analysis in isolated cells demonstrated that treatment was associated with increased glucose uptake in adipocytes, in particular those derived from epididymal fat, and in myocytes. Furthermore, analysis of gene expression in inguinal white adipose tissue (iWAT) 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.
Low doses of rosiglitazone also reduced inflammation, fibrosis, and atrophy in the tissues of aging mice. Analysis of gene expression in adipose depots, liver, muscle, and brain showed decreased levels of inflammatory genes and increased expression of genes encoding for factors involved in mitochondrial functionality and genome stability.
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.
Implications for Human Use
To assess whether the longevity effects observed in mice may correlate with outcomes in humans treated with PPARγ agonists, Dr. Mueller’s team performed a retrospective survival analysis of patients treated with another such drug: pioglitazone, which has been the thiazolidinedione of choice for the past 20 years. (Rosiglitazone was temporarily subject to prescribing restrictions in the United States due to safety concerns.)
The researchers analyzed the electronic medical records of 190,590 patients who were prescribed pioglitazone and 47,987 who were prescribed glimepiride—an insulin secretagogue with a distinct mode of action from PPARγ agonists. 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.
“Whether our retrospective studies can also infer the effects of thiazolidinediones on health span and overall longevity in healthy subjects remains to be determined through a prospective study,” Dr. Mueller notes. “Overall, however, our data support the use of low-dose PPARγ agonists as possible novel pharmacological interventions to counteract the deleterious effects of aging.”
