The National Institute on Aging Interventions Testing Program (ITP) was designed to be the most exhaustive testing framework and system to evaluate whether longevity molecules extend longevity in mice and understand the underlying mechanisms leading to those benefits.
The ITP involves the collaboration of three research labs running experiments in parallel. These labs conducted evaluations on a selection of promising longevity molecules, including rapamycin, metformin, nicotinamide riboside, and the SGLT-2 inhibitor canagliflozin, among others.
At the end of the study, only five of the molecules that the ITP studied were shown to increase longevity. One of the most eye-opening findings from the study was the results of acarbose.
The ITP showed that acarbose led to an increase in lifespan in the animal model they were studying. When acarbose was combined with the mTOR inhibitor rapamycin, it resulted in a significant increase in lifespan, which was even more pronounced than when acarbose was used alone.
Interestingly, while acarbose did lead to an extension of lifespan, the diabetes medication metformin failed to show positive results on lifespan.
Why would two medications that have seemingly similar effects on maintaining blood glucose levels have very different results in terms of the end goal of extending lifespan?
There seems to be something about the exact way that acarbose lowers postprandial glucose levels—through its effects on gut microbiota—which makes it a powerful healthspan-promoting molecule.
Here are the underlying mechanisms that we think contribute to acarbose’s ability to promote healthspan:
Acarbose works by blocking an enzyme called alpha-glucosidase, which helps digest and absorb carbohydrates in the small intestine. By inhibiting this enzyme, acarbose slows down the digestion and absorption of carbs, which can help regulate blood sugar levels and prevent spikes in blood glucose.
In studies of diabetes patients taking acarbose, we have observed an absolute decrease of 0.7% in HbA1c levels, which translates to approximately a 10% reduction in typical HbA1c values for diabetes patients. This reduction in blood glucose levels has a profound impact on longevity.
As we age, our bodies become less able to regulate glucose and insulin levels. High levels of glucose in the body can increase the risk of cardiovascular and metabolic problems and can also damage the endothelial cells that line our blood vessels.
The toxic effects of elevated glucose levels may be due to the increased production of mitochondrial reactive oxygen species (ROS). These molecules, which contain oxygen and can be either free radicals or non-radicals, are highly reactive and can cause damage to cells and tissues. This can lead to the development of diseases such as cancer, heart disease, and neurodegenerative disorders.
In addition, hyperglycemia-induced production of ROS can cause systemic damage to the cardiovascular system, contributing to complications associated with diabetes.
Acarbose lowers the risk of cardiovascular disease through its reduction of these glucose peaks and lowering the vascular damage incurred by elevated concentrations of glucose in the bloodstream.
By dampening the postprandial peaks in glucose, acarbose also indirectly increases insulin sensitivity—lower concentrations in glucose levels require less insulin to transport the glucose into the cell for energy. This is critically important for longevity.
Elevation in insulin corresponds to an elevation of a growth hormone called insulin-like growth factor-1 (IGF-1). Both insulin and IGF-1 play a role in promoting cellular growth. These hormones are often used by bodybuilders for their anabolic effects, which can help to increase muscle tissue. However, it is also known that bodybuilders have higher rates of early onset of age-related chronic diseases such as cancer and cardiovascular disease. This may be due to the fact that excessive growth signals can lead to the proliferation of unhealthy cells, including senescent and cancerous cells, in addition to healthy cells.
Through the understanding of Mikhail Blagosklonny’s hyperfunctionality theory of aging, we know that most disease states occur when cells excessively grow, overexpress and secrete certain molecules and proteins, and stimulate growth and replication of adjacent cells.
Excessive growth signals from elevated glucose, causing increasing amounts of insulin needed to metabolize that glucose, lead to the acceleration of disease states.
It is known that individuals with defective IGF-1 receptors, which do not recognize the IGF-1 hormone, have a lower incidence of cancer. This is because when these cells are exposed to IGF-1 hormone, they do not have the necessary receptors to recognize the hormone and trigger cellular hyperfunction and growth—ultimately increasing the individual’s healthspan.
This mechanism may contribute to the observed longevity benefits of acarbose, which has been shown to have a dampening effect on glucose and insulin signaling.
It is well established that the blunting of glucose levels can promote healthspan and longevity. However, metformin also delivers some of the same benefits. The ITP, however, did not show that metformin increased lifespan. There have to be other mechanisms outside of glucose regulation to explain the divergence in results in metformin and acarbose.
There is a growing body of evidence suggesting that imbalances in the microbiome, known as dysbiosis, drive aging.
The gut microbiota is the community of microorganisms that live in the digestive tract. It is known to play a role in many aspects of human health, including digestion, immune function, and metabolism.
Research has shown that the diversity of the gut microbiota tends to decrease with age, which can lead to a condition known as dysbiosis. Dysbiosis is an imbalance in the gut microbiota that can trigger low-grade inflammation and has been linked to the development of certain diseases, including cancer.
One potential mechanism by which dysbiosis may contribute to cancer development is through the presence of abnormal cells in the intestine (intestinal dysplasia). These abnormal cells may be a precancerous condition and may eventually progress to cancer.
Acarbose increases the amount of resistant starch that could not be broken down by the intestinal enzymes. Resistant starch enters the colon, where it is fermented by the gut microbiota, leading to an increase in the production of short-chain fatty acids (SCFAs). SCFAs may play a critical role in extending longevity and may also produce other signaling molecules that have been associated with longevity benefits.
The balance of gut microbiota has been shown to have numerous benefits, including the reduction of inflammation. There is increasing evidence that suggests a link between inflammation and the gut microbiota, and that modifying the gut microbiota can help reduce age-related chronic inflammation and promote healthspan. One way to do this is by using a medication like acarbose, which has been shown to help remodel the gut microbiota to optimal levels. In summary, maintaining a healthy gut microbiota balance through the administration of acarbose may help reduce inflammation and improve overall health and lifespan.
The downstream effects of inflammation reduction have significant implications for longevity. For example:
- Increased inflammatory activity has been linked to brain aging, but acarbose, a medication that inhibits the activation of the hypothalamic nuclear factor kappa B (NF-κB) inflammatory pathway, has been shown to delay aging in mice. Acarbose has been found to inhibit the activation of interferon-γ inducible protein-10, monocyte chemoattractant protein-1, macrophage-derived chemokine, and TNF-α, and to downregulate NF-κB-P65 activity in human monocytic THP-1 cells.
- Furthermore, the levels of IL-6 in patients with diabetes treated with acarbose are also significantly reduced.
- Adipose tissue is a significant source of inflammation. There is evidence that acarbose has the ability to curb adipose tissue inflammation.
Acarbose reduces the expression levels of inflammatory factors by increasing the abundance of beneficial bacteria. Many species of these anti-inflammatory bacteria are recognized as short-chain fatty acid-producing bacteria that exert anti-inflammatory effects. These findings provide strong evidence for the anti-inflammatory potential of acarbose.
Acarbose also increases concentrations of circulating glucagon-like peptide 1 (GLP-1). GLP-1 is a hormone that is produced in the gut in response to food intake. It helps regulate glucose metabolism, and has been shown to improve insulin sensitivity and reduce blood sugar levels in people with diabetes.
GLP-1 also seems to act directly on the vasculature, liver, myocardium, β cells, and brain to safeguard the structural and functional integrity of these organs in a way likely to slow aging and promote longevity.
Here’s the link to a more extensive write-up on the ITP findings on acarbose and rapamycin: