The most powerful tool to stop the acceleration of aging caused by mTOR dysfunction and cellular senescence.
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When the NIA tested over a dozen longevity molecules, acarbose was one of five molecules shown to increase lifespan, but how does it work? The story of acarbose as a longevity molecule lies at the intersection of its ability to augment our metabolic health and remodel our gut microbiota.
By: Daniel Tawfik
Identifying successful anti-aging interventions that have a discernible impact on lifespan is complicated. Aging is driven by multiple biological pathways. The complexity of the aging process and the lack of long-term studies, standard definitions, and reliable methods of measurement make it difficult to identify successful anti-aging interventions.
For this reason, the National Institute for Aging (NIA) decided to create one of the most comprehensive Interventional Testing Programs (ITP) for longevity drugs and to gain more clarity how these biological pathways interact.
The findings of the ITP on the synergistic effects of rapamycin and acarbose on mTOR, metabolic health, and the gut microbiota in relation to aging caught the attention of scientists seeking to understand the synergistic mechanisms driving aging.
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.
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 cannot be broken down by 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.
Mechanistically, we now have multiple pathways that acarbose seems to be working on, which comports with our understanding of aging as dysfunction in multiple interconnected biological pathways.
The results of the ITP study indicated that the combination of rapamycin and acarbose had the most significant impact on lifespan.
The rationale for combining rapamycin was initially to combine the insulin sensitizing effect of acarbose an antidote to the insulin-desensitizing effect of rapamycin.
Rapamycin is a drug that is believed to have anti-aging effects through the suppression of mTOR signaling. mTOR, or mechanistic target of rapamycin, is a protein that plays a role in cell growth and metabolism. When mTOR signaling is suppressed, it can lead to reduced cell growth and a slower rate of aging.
By contrast, acarbose, is likely to affect lifespan through pathways at least partly distinct from mTOR signaling. It was proposed that the combination of rapamycin and acarbose might have additive effects on lifespan through their complementary mechanisms of action.
Additionally, an earlier ITP study showed marked improvement of the microbiome of mice who were administered acarbose. An analysis of the fecal microbiome and metabolites of the acarbose-treated mice from the earlier study revealed shifts in the microbiota composition and increases in short-chain fatty acids that correlated with an increased lifespan of acarbose-treated animals.
The researchers evaluated the effect of the rapamycin and acarbose in combination given to mice starting at either 9 or 16 months. The 9-month mice had the greatest results, increasing the medium lifespan of female and male mice by 28% and 34%, respectively. The 16-month mice still increased the medium lifespan of both female and male mice by 13%.
In male mice, the combination of rapamycin and acarbose started at nine months and led to a longer lifespan than in either of the two prior groups of mice treated with rapamycin only, suggesting that this drug combination was more potent than either of its components used alone.
In females, lifespan in mice receiving both drugs was neither higher nor lower than that seen previously in rapamycin only, perhaps reflecting the limited survival benefits seen in prior cohorts of females receiving acarbose alone.
These results suggest that rapamycin and acarbose, taken together, boost the positive effects of each drug in the mouse model.
In additional studies conducted by three independent laboratories by the US National Institute on Aging's ITP, acarbose was shown to extend the lifespan of female mice by 5% and of male mice by 22%.
Out of 14 longevity molecules, the combination of rapamycin and acarbose were 2 of the 5 longevity molecules that extended lifespan. In three independent trials, the combination extended lifespan by 22%.
In a study of all longevity molecules, the combination of rapamycin and acarbose had the largest increase in lifespan—this has been seen in nearly all mammalian species—an average of 30% life extension.
While studies have long indicated that rapamycin is effective in extending lifespan, researchers are continually discovering how best to augment its longevity benefits. Exhaustive testing from the ITP confirms that, at the present time, acarbose stands out as the single best addition to a rapamycin longevity protocol. The two medications, when taken together, have the strongest data on their potential to increase lifespan. Those using rapamycin to promote cellular health and extend lifespan should not hesitate to discuss with their doctor adding acarbose to their regimen.
TAKE HOME POINTS
Complexity of Aging: Aging involves multiple biological pathways, making it difficult to pinpoint effective anti-aging interventions. The lack of long-term studies, standard definitions, and reliable measurement methods adds to this challenge.
National Institute for Aging's Interventional Testing Program (ITP): To address these challenges, the NIA initiated the ITP, aiming to be the most comprehensive testing framework for longevity drugs. This program studies the interaction between biological pathways and the effects of longevity drugs on mice.
Synergistic Effects of Rapamycin and Acarbose: Among the findings, the combination of rapamycin, an mTOR inhibitor, and acarbose showed a significant increase in lifespan in mice, more so than when either drug was used alone. The study highlights the importance of understanding the synergistic mechanisms driving aging.
Diverse Longevity Molecules Tested: The ITP evaluated various molecules for their potential to extend longevity, including rapamycin, metformin, nicotinamide riboside, and canagliflozin. Only five of these molecules were shown to increase longevity, with acarbose standing out for its effect when combined with rapamycin.
Longevity Mechanisms of Acarbose: The article details how acarbose contributes to longevity through several mechanisms, including reducing glucose spikes, lowering IGF-1 levels, remodeling the gut microbiome, reducing systemic inflammation, and enhancing cardiovascular health via GLP-1. Acarbose works by inhibiting the enzyme alpha-glucosidase, slowing down carbohydrate digestion and absorption, and thus managing blood sugar levels.
Testing Acarbose and Rapamycin Together: The combination of rapamycin and acarbose was found to be the most effective in extending lifespan, with the rationale being their complementary mechanisms of action on insulin sensitivity and mTOR signaling, as well as their effects on the gut microbiome.
Conclusion and Implications for Longevity Protocols: The combination of rapamycin and acarbose has shown the most significant impact on extending lifespan in mice, suggesting that this combination might be the most effective strategy currently known for promoting cellular health and longevity.
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