Optimizing Longevity Protocols: The Synergistic Potential of Rapamycin, Acarbose, and Metformin

In longevity research, many drugs have garnered significant attention for promoting lifespan: Rapamycin, Metformin, and Acarbose, being a few. While Rapamycin often emerges as the popular choice due to thorough research backing its anti-aging benefits, it does not have to be used in isolation. Combining Rapamycin with other longevity protocols may create synergistic effects that enhance its efficacy. Two potential options for such combinations are Metformin and Acarbose, which were initially developed for managing type 2 diabetes but are now gaining interest due to their potential longevity benefits.

Rapamycin is well-regarded for inhibiting the mammalian target of rapamycin (mTOR) pathway, a key regulator of cell growth, proliferation, and metabolism. This inhibition has been shown to extend lifespan in various organisms by promoting cellular processes such as autophagy, reducing inflammation, and improving cellular resistance. However, the strategic pairing of Rapamycin with other compounds like Metformin and Acarbose could amplify these effects.

As researchers analyze the complex mechanisms underlying Acarbose and Metformin, several questions emerge: Could the strategic coupling of either of these drugs with Rapamycin extend survival by delaying the onset of aging? Is one more effective than the other when it comes to longevity? Considering they both work on glycemic control, is there a reason to take both?

This research review will explore distinctive mechanisms of action of Metformin and Acarbose, highlighting both their similarities and differences. It will present scientific evidence supporting their benefits for longevity, particularly when used in conjunction with Rapamycin. Insights will be offered on the most suitable protocols for various individuals and the most effective combinations of these treatments. Additionally, the discussion will explore why Acarbose might be the preferred choice for most people, while a specific subset may continue to benefit from Metformin.

Understanding Type 2 Diabetes (T2D)

Acarbose and Metformin are medications that primarily manage blood glucose levels in Type 2 Diabetes (T2D). T2D occurs when blood glucose (sugar) levels are higher than normal because insulin does not work as efficiently. Usually, after eating, the digestive system breaks down carbohydrates into glucose, which enters the bloodstream. Insulin is then released to help cells take up glucose from the blood and use it for energy. In T2D, the body's responsiveness to insulin decreases, leading to high blood sugar levels—this has a number of negative implications for longevity.

Insulin is required in different amounts to mediate various bodily processes. For example, between 30 to 500 microunits per milliliter (μU/mL) of insulin is needed for glucose uptake by fat and muscle tissues. When blood sugar levels rise after a meal, insulin signals the liver to suppress glucose production, requiring about 10 to 50 μU/mL in the portal vein (which carries blood from the digestive organs to the liver). Additionally, low quantities of insulin, around 1 to 20 μU/mL, are needed to prevent fat breakdown, as there is no need for body stores to be mobilized after a meal.

In T2D, the body's tissues and cells are less responsive even when insulin is released in adequate amounts. This decreased sensitivity to insulin hinders many insulin-dependent processes, such as glucose uptake, the suppression of glucose production, and fat breakdown. The imbalance between these processes results in hyperglycemia (high blood sugar).

Differential Mechanisms of Action for the Management of Type 2 Diabetes (T2D)

Studies have shown that Acarbose and Metformin can lower Hemoglobin A1c (HbA1c), a marker of average blood sugar levels over several months. Lowering HbA1c is crucial for reducing the risk of diabetes-related complications such as nerve damage, kidney problems, and eye disease. 

However, both Acarbose and Metformin work differently in managing T2D. Acarbose slows carbohydrate digestion in the intestine, reducing post-meal blood sugar spikes. Metformin, on the other hand, reduces liver glucose production and enhances insulin sensitivity in peripheral tissues. Let's briefly dive into these mechanisms:

Acarbose

Acarbose tackles Type 2 Diabetes by re-sensitizing body tissues and cells to insulin. To enable glucose to be used as an energy source, the body needs to break down starch and oligosaccharides (complex sugars) in the intestines because only monosaccharides (simple sugars) can be absorbed into the bloodstream. Oligosaccharides are broken down into monosaccharides by proteins called α-glucosidases found in the small intestine. [2]

Acarbose is similar in structure to natural oligosaccharides but has a higher affinity for the α-glucosidase proteins. It can bind to these proteins and block their availability to break down natural oligosaccharides from food. As a result, fewer monosaccharides are formed, and less insulin is needed to metabolize them. Hence, Acarbose works by inhibiting the enzymes (alpha-glucosidases) in the small intestine that are responsible for breaking down complex carbohydrates into simple sugars like glucose. This inhibition slows the absorption of carbohydrates, leading to a reduction in postprandial (after-meal) blood glucose levels. This makes them more receptive to insulin's function of facilitating glucose uptake from the blood. [2]

In later stages of T2D, Acarbose can also help reduce stress on β-cells, allowing them to function more efficiently. β-cells are specialized cells in the pancreas that produce insulin by producing pro-insulin, an inactive precursor. When the right signals are present, pro-insulin is cleaved into mature insulin and released into circulation.

In the initial stages of T2D, when insulin resistance develops, β-cells become hyperactive as they try to produce more insulin to compensate for insulin resistance. Acarbose lowers this stress and helps them return to a state of normalcy. This can be seen through the lower levels of pro-insulin release in patients with T2D on Acarbose.

Interestingly, pro-insulin is also a risk factor for cardiovascular disease. Hence, by lowering pro-insulin levels via action on β-cells, Acarbose can also improve the prognosis of patients with T2D in the cardiovascular realm. [3, 4]

Metformin

Metformin uses a different approach to managing Type 2 Diabetes. Metformin works by lowering the amount of glucose that the liver produces. [5] In a complex process called gluconeogenesis, the liver converts non-carbohydrate sources like fats and proteins into glucose, typically initiated when a person is fasting, and there is not enough dietary sugar available to procure glucose for body tissues. [5]

Besides inhibiting gluconeogenesis, Metformin also helps the body use insulin better. It makes muscles and fat cells more sensitive to insulin so they can take in more glucose from the blood. Rossetti et al. (1990) studied three groups of rats—healthy control rats, diabetic rats without treatment, and treated with Metformin. Diabetic rats had higher blood sugar levels compared to healthy rats. Metformin treatment helped the diabetic rats' blood sugar levels improve, even though it did not increase their insulin levels. Metformin increased the diabetic rats' ability to use insulin effectively. In particular, it increased the activity of a specific protein called insulin receptor tyrosine kinase in the muscle cells of diabetic rats. The insulin receptor tyrosine kinase upregulation was closely linked to improved insulin sensitivity and increased glucose storage (glycogen) in the muscle. [6] Finally, Metformin also slows down glucose absorption from the gut after a meal. Collectively, these actions help keep blood sugar levels in check and improve the body's response to insulin.

Longevity Benefits of Acarbose and Metformin

Metformin and Acarbose have long been used in T2D management. However, they have garnered attention in recent years for a different reason. In addition to their effects on blood glucose levels, both medications have gained momentum for their potential benefits in longevity. Let us delve deeper into some of these findings.

Acarbose 

Acarbose works by inhibiting the enzyme α-glucosidase, which breaks down complex carbohydrates into simpler sugars. This delay in carbohydrate absorption helps blunt post-meal spikes in blood glucose levels, leading to improved glycemic control. Maintaining stable blood glucose levels is essential for overall health and can help prevent or delay diabetes-related complications, negatively impacting lifespan.

As discussed in our , high glucose levels can exacerbate aging. [7] Elevated glucose can damage endothelial cells lining blood vessels, disrupting circulation and promoting the production of harmful reactive oxygen species (ROS). These ROS molecules can trigger cellular damage, leading to age-related diseases such as cardiovascular diseases, cancer, and neurodegenerative disorders.

Studies have shown that Acarbose can protect against elevated glucose's damaging effects on mice's cardiovascular health. McCarty & DiNicolantonio (2014) believe the medication exerts cardioprotective effects by promoting the production of glucagon-like peptide 1 (GLP-1) in the gut. GLP-1 helps protect blood vessels, the liver, heart, insulin-producing cells, and the brain, which are linked to longer lifespans. [8]

Study Insights: Acarbose Enhances GLP-1 Secretion and Improves Glycemic Control in Type 2 Diabetes

GLP-1 (glucagon-like peptide-1) has garnered significant attention in recent years, particularly with the advent of GLP-1 receptor agonists like Ozempic (semaglutide) for weight loss and glucose management.

Study Insights: Acarbose Enhances GLP-1 Secretion and Improves Glycemic Control in Type 2 Diabetes

The therapeutic potential of GLP-1 (glucagon-like peptide-1) has garnered significant attention in recent years, particularly with the advent of GLP-1 receptor agonists like Ozempic (semaglutide) for weight loss and glucose management.

GLP-1 is an incretin hormone that plays a crucial role in glucose metabolism. Secreted by the intestinal L-cells in response to food intake, GLP-1 enhances insulin secretion from pancreatic beta cells, particularly in a glucose-dependent manner, which helps lower blood sugar levels. Additionally, GLP-1 inhibits the release of glucagon, a hormone that increases blood glucose levels, thereby contributing to better glycemic control.

Beyond its effects on glucose metabolism, GLP-1 slows gastric emptying, which prolongs the time food remains in the stomach. This delay in gastric emptying not only aids in postprandial glycemic control by moderating the rate of glucose absorption but also contributes to the sensation of fullness, or satiety. The promotion of satiety by GLP-1 helps reduce food intake, which is a significant factor in its weight loss benefits. This multifaceted action makes GLP-1 receptor agonists effective pharmaceutical agents for treating type 2 diabetes (T2D) and obesity.

The use of Ozempic is outside of the scope of this article, but we have written about some of the safety considerations: GLP-1 use in the context of healthspan promotion. While the exogenous administration of GLP-1 analogs remains an area of active research, acarbose could potentially be a safer alternative for its ability to stimulate endogenous GLP-1 secretion.

Study Design and Participant Profile

Researchers at the University of Copenhagen’s Center of Metabolic Research conducted a study titled "Acarbose-Induced Glucagon-Like Peptide-1 Secretion Contributes to the Glucose-Lowering Effect of Acarbose." This study examined the effects of acarbose on glucose metabolism and hormone responses in metformin-treated patients with type 2 diabetes (T2D). Employing a double-blinded, placebo-controlled, randomized, cross-over design, the study ensured robust and unbiased results. Fifteen participants with T2D, aged 57 to 85 years, with body mass indices (BMI) from 23.6 to 34.6 kg/m² and HbA1c levels between 5.8% and 8.9%, were enrolled. This demographic represents a typical population of older adults with T2D, characterized by complex health needs and comorbidities [9].

Treatment Protocol

Participants underwent two 14-day treatment periods with acarbose, uptitrated to 100 mg three times daily (TID), and a placebo, separated by a 6-week wash-out period.

Key Findings

The study revealed several significant outcomes:

• Reduction in Fasting and Postprandial Glucose: Acarbose significantly lowered fasting plasma glucose levels and reduced postprandial glucose excursions compared to the placebo (P<0.0001). This underscores acarbose's efficacy in enhancing overall glycemic control.

• Enhanced GLP-1 Response: Postprandial GLP-1 response almost doubled with acarbose treatment (P=0.0032). GLP-1 is a crucial incretin hormone that stimulates insulin secretion in response to food intake, playing a vital role in maintaining glucose homeostasis. This increase in levels of GLP-1 is very different from the use of semaglutide. Clinical trials have shown that semaglutide significantly increases GLP-1 levels. For example, in the PIONEER 1 trial, oral semaglutide treatment resulted in a 300-400% increase in GLP-1 levels from baseline in patients with type 2 diabetes over a period of 26 weeks​ [10].

• Hormonal Modulations: Acarbose treatment resulted in a significant reduction in postprandial glucose-dependent insulinotropic polypeptide (GIP) levels (P<0.0001) and delayed gastric emptying (P=0.0395). GIP, another incretin hormone, typically increases insulin secretion in response to meals but can also enhance glucagon secretion and lipid storage. Lowering GIP levels may reduce these undesired effects, contributing to better metabolic outcomes. The delay in gastric emptying induced by acarbose slows the rate at which food leaves the stomach and enters the small intestine, thereby extending the absorption period of glucose. This extended absorption period helps moderate the rise in blood glucose levels after meals, improving postprandial glucose control and reducing glucose spikes that are common in T2D patients.

• Role of GLP-1 in Glucose Regulation: To further elucidate GLP-1's role in glucose regulation, the study used exendin(9-39)NH2, a GLP-1 receptor antagonist. This compound blocks the action of GLP-1, thereby allowing researchers to assess the hormone's specific contribution to glucose control. The study found no absolute difference in exendin(9-39)NH2-induced postprandial plasma glucose changes between the acarbose and placebo treatment periods (P=0.54). However, the relative contribution of GLP-1 to glucose tolerance was significantly higher during acarbose treatment (P=0.042). This indicates that acarbose’s glucose-lowering effect is partly mediated by its stimulation of GLP-1 secretion. Essentially, the enhanced GLP-1 response during acarbose treatment plays a significant role in improving postprandial glucose tolerance, highlighting the importance of this hormone in the drug's overall efficacy.

These findings reinforce the potential of acarbose as an effective adjunctive therapy in T2D management, particularly beneficial for patients requiring enhanced incretin response and improved postprandial glucose control. It also provides the basis for the utilization of acarbose as a potentially safer alternative to exogenous GLP-1 medications like Ozempic.

Gut Microbiome Benefits of Acarbose

Besides its effects on blood glucose levels, Acarbose has also been shown to alter the gut microbiome composition, which is increasingly recognized as crucial for overall health and longevity. The gut microbiome is the community of bacteria in our digestive system, performing many vital functions to keep us healthy. Acarbose can selectively promote the growth of beneficial gut bacteria, such as Bifidobacterium and Lactobacillus species, by inhibiting the breakdown of complex carbohydrates. 

The National Institute for Aging’s Interventional Testing Program investigated Acarbose's lifespan-enhancing effects in male and female mice. The ITP is a collaborative research initiative designed to investigate potential interventions that may extend lifespan and improve healthspan. Established in 2003, the ITP conducts rigorous and standardized testing of various compounds across multiple independent research sites. The goal is to identify treatments that can delay aging and reduce the incidence of age-related diseases.

The ITP uses genetically heterogeneous mice, which more closely resemble the genetic diversity found in the human population compared to inbred mouse strains. This approach increases the generalizability of the findings. The program employs standardized protocols across multiple sites to ensure reproducibility and reliability of results. Beyond measuring lifespan, the ITP also assesses healthspan, looking at various markers of health and disease, such as cancer incidence, immune function, and metabolic health.

In their research into the longevity effects of acarbose, the ITP found a gender-specific impact, extending lifespan by around 20% in male mice compared to 5% in female mice. Regardless of gender variations, the researchers attributed these anti-aging effects to changes in the gut microbiome [11].

Acarbose causes more starch to pass from the small intestines to the large intestines, where many gut bacteria reside. This allows these bacteria to ferment more starch, producing more short-chain fatty acids (SCFAs). The researchers found that the abundance of a particular group of bacteria called Muribaculaceae increased significantly in mice treated with Acarbose. This change in the gut microbiome was linked to higher levels of the SCFA called propionate in the mice's feces. The overall levels of SCFAs in the feces, including acetate, butyrate, and propionate, were correlated with the mice's lifespan. The study suggests that acarbose-induced changes to the gut microbiome and increases in SCFAs may be part of how the drug increases lifespan in mice [11].

Mechanisms Through Which SCFAs Influence Longevity

Gut Health

Short-chain fatty acids (SCFAs), primarily acetate, propionate, and butyrate, play a crucial role in maintaining gut health by serving as key regulators of the intestinal environment. These metabolites are produced through the fermentation of dietary fibers by gut microbiota. By providing an energy source for colonocytes, the cells lining the colon, SCFAs support the integrity of the gut barrier.

One of the significant contributions of SCFAs is their ability to maintain a balanced and healthy microbiome. They selectively promote the growth of beneficial bacteria such as Bifidobacteria and Lactobacilli, while inhibiting the proliferation of pathogenic bacteria like Clostridium difficile. This selective promotion enhances microbiota diversity, which is vital for a resilient gut ecosystem capable of withstanding various stressors and pathogens [12].

Moreover, SCFAs stimulate the production of mucus by goblet cells in the intestinal lining. Mucus acts as a protective layer that shields the epithelium from mechanical damage and pathogen invasion. Additionally, SCFAs upregulate the expression of tight junction proteins such as occludin and claudins. These proteins are essential components of the tight junctions that seal the spaces between epithelial cells, preventing the passage of harmful substances into the bloodstream. By strengthening these barriers, SCFAs reduce the risk of leaky gut syndrome, a condition where increased intestinal permeability leads to systemic inflammation and associated health issues [13].

Anti-Inflammatory Effects

Butyrate, in particular, has potent anti-inflammatory properties. One of the key mechanisms by which butyrate exerts its anti-inflammatory effects is through the inhibition of nuclear factor kappa B (NF-κB), a protein complex that plays a critical role in regulating the immune response to infection. NF-κB controls the production of pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1 beta (IL-1β). By inhibiting NF-κB, butyrate reduces the production of these pro-inflammatory cytokines, thus mitigating inflammatory responses [13].

Simultaneously, butyrate promotes the production of anti-inflammatory cytokines, such as interleukin-10 (IL-10) and transforming growth factor-beta (TGF-β). These cytokines help to resolve inflammation and maintain immune balance. IL-10, for instance, is crucial for controlling inflammatory responses and preventing tissue damage during infections. TGF-β plays a vital role in regulating the immune system and promoting tissue repair.

The anti-inflammatory effects of butyrate are particularly significant in the context of chronic low-grade inflammation, which is a hallmark of aging and is associated with various age-related diseases, including cardiovascular disease, type 2 diabetes, and neurodegenerative disorders. By reducing chronic inflammation, butyrate contributes to healthier aging and may help mitigate the progression of inflammatory diseases [13].

Immune Modulation

SCFAs modulate the immune system by influencing the differentiation and function of immune cells such as regulatory T cells (Tregs). SCFAs exert their immunomodulatory effects through multiple mechanisms. One primary pathway involves the inhibition of histone deacetylases (HDACs), which leads to increased acetylation of histone proteins and alterations in gene expression. This epigenetic modification promotes the differentiation of naïve T cells into Tregs, which are essential for maintaining tolerance to self-antigens and preventing autoimmune reactions.

Butyrate, in particular, has been shown to enhance the proliferation and suppressive function of Tregs. It upregulates the expression of Foxp3, a transcription factor critical for Treg development and function. Increased Foxp3 expression enhances the ability of Tregs to suppress inflammatory responses and maintain immune tolerance. Moreover, SCFAs, including butyrate, stimulate the production of anti-inflammatory cytokines, such as interleukin-10 (IL-10), further contributing to an anti-inflammatory environment [14].

The modulation of immune cell function by SCFAs is essential for a balanced immune response, protecting the body against infections while preventing overactive immune responses that can lead to chronic inflammation and autoimmune diseases. This balance is crucial for overall health and longevity, as chronic inflammation is linked to numerous age-related diseases and a decline in immune function.

Metabolic Health

One of the primary ways SCFAs improve metabolic health is by enhancing glucose metabolism and insulin sensitivity. SCFAs, especially propionate and butyrate, activate free fatty acid receptors (FFAR2 and FFAR3) on enteroendocrine cells, leading to the secretion of glucagon-like peptide-1 (GLP-1) and peptide YY (PYY). We saw from the University of Copenhagen study how acarbose increased levels of GLP-1 and its corresponding effects on lowering glucose levels. Additionally, SCFAs enhance glucose uptake in peripheral tissues, such as muscle and adipose tissue, by upregulating glucose transporter type 4 (GLUT4) expression. This improved glucose uptake contributes to better glycemic control and increased insulin sensitivity [15].

SCFAs also have a significant impact on lipid metabolism. They influence lipid homeostasis by reducing serum cholesterol and triglyceride levels. This effect is mediated through several mechanisms, including the inhibition of hepatic lipogenesis, the process by which fatty acids are synthesized in the liver. SCFAs inhibit the activity of enzymes involved in lipogenesis, such as acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS), leading to reduced synthesis and accumulation of lipids in the liver. Furthermore, SCFAs increase the expression of genes involved in lipid oxidation, promoting the breakdown of fatty acids for energy production.

These metabolic benefits of SCFAs protect against metabolic diseases such as obesity and type 2 diabetes. By improving insulin sensitivity and glucose metabolism, SCFAs help maintain healthy blood sugar levels and prevent insulin resistance, a precursor to type 2 diabetes. Additionally, by reducing serum cholesterol and triglyceride levels, SCFAs lower the risk of cardiovascular diseases associated with metabolic disorders [16].

Epigenetic Regulation

SCFAs, particularly butyrate, are recognized for their role as histone deacetylase inhibitors (HDACi). Histone deacetylases (HDACs) are enzymes that remove acetyl groups from histone proteins, leading to a more condensed chromatin structure and reduced gene expression. By inhibiting HDACs, butyrate induces hyperacetylation of histones, resulting in a more relaxed chromatin structure and increased gene transcription [17].

This epigenetic regulation by butyrate has profound effects on cellular function and longevity. By modifying chromatin structure, butyrate influences the expression of a wide array of genes involved in cell proliferation, differentiation, and apoptosis. For instance, butyrate-mediated inhibition of HDACs can activate tumor suppressor genes, thereby exerting anti-cancer effects. It can also enhance the expression of genes involved in cell cycle regulation and DNA repair, promoting genomic stability and reducing the risk of mutations [17].

Furthermore, the epigenetic modulation by butyrate supports improved cellular function by enhancing mitochondrial activity and biogenesis. Mitochondria are critical for energy production, and their efficiency is vital for maintaining cellular health and preventing metabolic disorders. By promoting the expression of genes involved in mitochondrial function, butyrate helps maintain optimal energy levels and supports cellular metabolism.

Butyrate's role as an HDACi also has implications for longevity. By enhancing the expression of genes associated with stress resistance and anti-inflammatory pathways, butyrate contributes to cellular resilience against oxidative stress and inflammation, both of which are key factors in the aging process. Additionally, the regulation of autophagy-related genes by butyrate helps in the removal of damaged cellular components, thereby preserving cellular integrity and function over time.

Mitochondrial Function

SCFAs play a crucial role in enhancing mitochondrial function and biogenesis, which are essential processes for efficient energy production and cellular health.

Mitochondria, often referred to as the powerhouses of the cell, are responsible for generating adenosine triphosphate (ATP), the primary energy currency of the cell. SCFAs, particularly butyrate, promote mitochondrial function by upregulating the expression of genes involved in mitochondrial respiration and energy production. This includes genes encoding components of the electron transport chain, which is critical for ATP synthesis. Enhanced mitochondrial function ensures that cells have a sufficient supply of energy to perform various physiological processes efficiently.

Additionally, SCFAs stimulate mitochondrial biogenesis, the process by which new mitochondria are formed within cells. This is achieved through the activation of key regulatory pathways, such as the peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) pathway. PGC-1α is a transcriptional coactivator that regulates the expression of genes involved in mitochondrial biogenesis and oxidative metabolism. By activating PGC-1α, SCFAs increase the number of mitochondria in cells, enhancing their capacity for energy production [18].

Beyond improving energy production, SCFAs also reduce oxidative stress, a condition characterized by the excessive accumulation of reactive oxygen species (ROS). High levels of ROS can damage cellular components, including lipids, proteins, and DNA, leading to cellular dysfunction and contributing to the aging process. SCFAs help mitigate oxidative stress by enhancing the expression of antioxidant enzymes, such as superoxide dismutase (SOD) and catalase. These enzymes neutralize ROS, thereby protecting cells from oxidative damage [18].

The combined effects of enhanced mitochondrial function, increased mitochondrial biogenesis, and reduced oxidative stress contribute significantly to cellular health and longevity. By ensuring efficient energy production and protecting against oxidative damage, SCFAs help maintain the functional integrity of cells over time, reducing the risk of age-related diseases and promoting a longer, healthier life [18].

Enhanced Cognitive Function

SCFAs, particularly butyrate, have been shown to improve brain function by enhancing neurogenesis, reducing neuroinflammation, and improving synaptic plasticity, which can help maintain cognitive function with age [19].

These effects are crucial for maintaining cognitive function, especially as the brain ages.

Neurogenesis, the process of generating new neurons, is vital for learning, memory, and overall cognitive health. Butyrate has been found to promote neurogenesis in the hippocampus, a brain region essential for these cognitive functions. It does so by increasing the expression of brain-derived neurotrophic factor (BDNF), a protein that supports the survival, growth, and differentiation of neurons. Enhanced BDNF levels contribute to the formation of new neural connections and the integration of new neurons into existing circuits, which are critical for maintaining cognitive flexibility and resilience against age-related decline [19].

In addition to promoting neurogenesis, butyrate has potent anti-inflammatory properties that benefit brain health. Neuroinflammation, characterized by the activation of microglia and the release of pro-inflammatory cytokines, is a common feature of neurodegenerative diseases and cognitive decline. Butyrate reduces neuroinflammation by inhibiting the production of pro-inflammatory cytokines, such as interleukin-1 beta (IL-1β) and tumor necrosis factor-alpha (TNF-α), through the inhibition of nuclear factor kappa B (NF-κB) signaling. By dampening these inflammatory pathways, butyrate helps protect neurons from inflammatory damage and supports a healthier brain environment [19].

Synaptic plasticity, the ability of synapses to strengthen or weaken over time, is fundamental to learning and memory. Butyrate enhances synaptic plasticity by increasing histone acetylation, which alters gene expression to favor synaptic growth and function. This epigenetic modulation facilitates the formation and maintenance of synaptic connections, enhancing the brain's capacity to adapt and store new information. Improved synaptic plasticity is associated with better cognitive performance and a reduced risk of cognitive decline with aging [19].

Some studies suggest that Acarbose may have similar effects to calorie restriction (CR), a well-known intervention that can extend lifespan in various animal models. By limiting carbohydrate absorption, Acarbose may trigger metabolic adaptations that mimic the beneficial effects of CR, such as improved insulin sensitivity, reduced oxidative stress, and enhanced cellular repair mechanisms. These adaptations may contribute to the medication's potential longevity-enhancing effects. Arya et al. (2023) administered Acarbose at a dose of 30 mg/kg of body weight to both young (4 months old) and old (24 months old) rats for six weeks. [12] They measured various markers of aging and oxidative stress in both control and treated rats.

Acarbose vs Caloric Restriction

Some studies suggest that Acarbose may have similar effects to calorie restriction (CR), a well-known intervention that can extend lifespan in various animal models. By limiting carbohydrate absorption, Acarbose may trigger metabolic adaptations that mimic the beneficial effects of CR, such as improved insulin sensitivity, reduced oxidative stress, and enhanced cellular repair mechanisms. These adaptations may contribute to the medication's potential longevity-enhancing effects. Arya et al. (2023) administered Acarbose at a dose of 30 mg/kg of body weight to both young (4 months old) and old (24 months old) rats for six weeks [20]. They measured various markers of aging and oxidative stress in both control and treated rats. The results showed that Acarbose improved several measures of antioxidant activity, such as the ferric-reducing ability of plasma (FRAP). FRAP is a biological assay that measures a sample's antioxidant capacity or activity, particularly in biological fluids like plasma or serum. It is based on the principle that antioxidants can chemically modify iron ions in the solution to a blue-colored complex. The intensity of the blue color is used as a proxy of the antioxidants in the fluid—the more blue the solution, the more antioxidants are present. In the study, both elderly and young mice treated with Acarbose showed greater blue signals in the FRAP assay relative to their control counterparts [20].

Acarbose treatment also significantly decreased Reactive Oxygen Species (ROS) in mice of both age groups relative to the controls. Interestingly, the effects of Acarbose were most prominent in aged mice, suggesting that Acarbose may be able to slow down some of the adverse effects of aging by helping to better regulate blood sugar levels, similar to how CR works [20].

The Interventional Testing Program demonstrated an increase in lifespan in the animal models,  these studies show that acarbose mediates these effects by potentially promoting the production of beneficial hormones like GLP-1 and altering the gut microbiome composition. The drug appears to have CR-like effects, providing antioxidant activity, reducing oxidative stress, and mitigating age-related changes, especially in older individuals. The multifaceted mechanisms by which Acarbose exerts its anti-aging effects, mainly through modulating glucose metabolism and the gut microbiome, make it a promising intervention for longevity.

Metformin

Similar to Acarbose, Metformin has garnered interest due to its potential longevity benefits and neuroprotective effects. Metformin enhances insulin sensitivity in peripheral tissues (muscles and adipose or fat tissue) and reduces insulin resistance. Insulin resistance is a hallmark of aging and contributes to various age-related diseases. This is because insulin resistance is linked to inflammation and stress inside the body, which are key factors that contribute to aging [21]. Insulin resistance is also inversely correlated with telomere length. In other words, the greater the level of insulin resistance, the shorter the telomere length in body cells tends to be.

As telomeres are like caps on the end of our chromosomes (organizational units that hold DNA), made up of repeating DNA sequences [22]. They protect our chromosomes from damage and help them stay intact. Every time our cells divide, telomeres get shorter. This shortening process is a natural part of aging. As they progressively shorten across cellular divisions, they eventually reach a threshold called the 'Hayflick limit.' Once this limit is reached, cells enter a state of 'senescence' where they stop dividing. Senescent cells are not dead per se. Rather, they exist in a 'zombie-like' state, releasing a constellation of pro-aging molecules termed the senescence-associated secretory phenotype (SASP). By lowering insulin resistance, Metformin can, hence, attenuate telomere shortening to delay aging.

The effects of Metformin in delaying telomere shortening and cellular senescence have been reported in several studies. Wang et al. (2024) investigated the effects of Metformin on aging astrocytes. Astrocytes are star-shaped cells that mediate several physiological processes to support neurons (nerve cells) in the brain. As one ages, these cells start to become increasingly senescent. Senescent astrocytes can contribute to neurodegenerative disorders like Parkinson's disease (PD). Apart from astrocytes, the mitochondria is another structure that gets affected with age. [23] Mitochondria are components found within cells that serve as the 'energy powerhouses.' They convert the energy in our raw food to a usable form of energy known as ATP. As mitochondria age, they can become less efficient in producing ATP and more prone to dysfunction. During this time, a protein called Mitofusin 2 (Mfn2) plays a crucial role in maintaining mitochondrial health and function.

In the study, the researchers grew astrocytes under two different conditions. They were maintained for a long time in one condition to promote senescence naturally. The cells were treated with specific chemicals to induce premature senescence and aging in the second condition. Additionally, the researchers used a mouse model of Parkinson's Disease (PD) to see how Metformin affects astrocyte aging in cells and living animals. The functioning of mitochondria was also assessed. Finally, genetic tools were used to manipulate a protein called cGAS in specific brain regions to understand how Metformin affected astrocyte aging.

The researchers found that Metformin slowed astrocyte aging in cell cultures and PD mice models. It exerted this anti-aging effect by restoring normal mitochondrial function. This restorative process involves the release of Mfn2, which leads to the inactivation of cGAS-STING, a pathway that accelerates astrocyte aging and contributes to nerve cell damage. Metformin was also found to protect dopamine neurons - the cells usually damaged in PD, and improve the behavior of mice with PD symptoms by reducing the number of aging astrocytes. These findings suggest that Metformin could be a valuable treatment for diseases where aging astrocytes play a role, such as PD and other neurodegenerative conditions related to aging.

Apart from reverting mitochondrial dysfunction, Metformin also promotes the synthesis of new mitochondria in the face of aging. This has to do with how it interacts with the Electron Transport Chain (ETC) complexes in the mitochondria. The ETC is a series of protein complexes found within the structures of mitochondria through which electrons (charged particles) pass to generate energy in the form of ATP. To better understand the function of the ETC, let us draw an analogy.

Imagine a group passing a bucket of water from one person to the next. This bucket of water represents the energy (in the form of electrons) being transported. At the start of the line, one person takes the bucket and hands it off to the next person. This first person represents the first complex in the ETC, accepting the electrons and passing them on. As the bucket passes down the line, each person (representing the next complex in the chain) takes a small amount of energy from the electrons before handing the bucket to the next person. Finally, at the end of the line, the last person uses the remaining energy to produce ATP, the large amount of energy needed by the cell.

If there is any disruption or problem in the line of people passing the bucket, the entire process gets interrupted, and the final amount of ATP produced will be reduced. This is precisely what Metformin does. Vial et al. (2019) described the mechanisms by which Metformin interacts with complexes of the ETC. [24] When the medication enters the body, it binds to and inhibits the activity of the ETC's first complex, also known as the NADH oxidoreductase. 

This inhibition can reduce the efficiency of the ETC, leading to a decrease in ATP production. Hence, even if the body is sufficiently fueled, Metformin reduces the ability of the mitochondrial ETC to extract adequate amounts of energy from it, 'tricking' the cell into thinking that it has less energy than it has. When energy levels run low, a protein called Adenosine Monophosphate-Activated Protein Kinase (AMPK) springs into action.

AMPK activation improves mitochondrial function by increasing mitochondrial biogenesis (synthesis of new mitochondria). This helps maintain cellular energy balance, which is crucial for delaying cellular aging. Kristensen et al. (2013) gave Metformin to mice that had defective AMPK (AMPK KD mice) and normal wild-type mice (WT) for two weeks. They found that the AMPK KD mice had reduced mitochondrial respiration and protein levels compared to the WT mice. When Metformin was administered, the AMPK KD mice demonstrated improved respiration and use of energy resources. The levels were brought back up to those in the WT mice. This suggests that Metformin treatment can enhance mitochondrial respiration in mice with mitochondrial deficiency, even for a mere two-week period. [25]

Apart from altering cellular energetics, Metformin also modulates ROS production. [24] The mitochondrial ETC is not only involved in ATP production but also in the generation of reactive oxygen species (ROS). ROS are highly reactive molecules containing oxygen, such as superoxide anions and hydrogen peroxide, which can damage cells and tissues through oxidative stress. Electrons passing through complexes 1 and 3 of the ETC can react with oxygen to form superoxide anions. Accumulation of these anions can lead to oxidative stress, harming cells and tissues. Metformin can reduce the formation of these ROS by directly inhibiting complex 1. However, this impact on the mitochondria can in some situations be more nuanced.

Metformin can be referred to as an "AMPK trickster" due to its ability to make AMPK perceive a lower energy state than actually exists. When Complex 1 of the Electron Transport Chain (ETC) is inhibited by Metformin, it reduces the flow of electrons through this complex. This reduction decreases the potential for oxidative stress and slows down ATP production. Interestingly, this state of reduced activity prompts the mitochondria to undergo biogenesis (creating new mitochondria), potentially leading to a browning effect of tissues, indicating increased mitochondrial activity. This mimics a calorie-restricted environment, where the body adapts to a lower energy intake by improving the efficiency and health of mitochondria. In such an environment, uncoupling proteins (UCP1 and UCP2) may be upregulated. These proteins help manage energy production and reduce oxidative stress by allowing protons to re-enter the mitochondrial matrix without producing ATP, acting as a safety valve.

When Metformin temporarily inhibits complex 1, several beneficial effects are observed. These include increased AMPK activity, which promotes glucose uptake and fatty acid oxidation. In the context of a fasted or very low-carb individual, this could promote gluconeogenesis, the process of generating glucose from non-carbohydrate sources. Additionally, temporary inhibition supports mitochondrial biogenesis, reduces oxidative stress, and helps maintain cellular energy balance.

However, in some cases, chronic inhibition of complex 1 by Metformin can have adverse effects. Long-term decreases in ATP production can impair the function of tissues with high energy demands, such as muscles and the brain. Furthermore, chronic inhibition can cause electron leakage from the ETC, leading to increased ROS generation. This excess ROS can damage cellular components, including DNA, proteins, and fats, ultimately leading to mitochondrial dysfunction.

To compensate for this, the cells in our bodies may try to increase the number of mitochondria via mitochondrial biogenesis. However, this compensatory mechanism is energy-intensive and may not fully restore normal mitochondrial function. The adverse effects of chronic Metformin exposure on mitochondrial bioenergetics and ROS production can contribute to various pathological conditions, including neurodegenerative diseases, cardiovascular complications, insulin resistance, and metabolic disorders.

To compensate for this, the cells in our bodies may try to increase the number of mitochondria via mitochondrial biogenesis. However, this compensatory mechanism is energy-intensive and may not fully restore normal mitochondrial function. The adverse effects of chronic Metformin exposure on mitochondrial bioenergetics and ROS production can contribute to various pathological conditions, including neurodegenerative diseases, cardiovascular complications, insulin resistance, and metabolic disorders.

Serra et al. (2020) found that a prolonged duration of Metformin therapy (for at least 18 months) in older veterans with diabetes was associated with an elevated risk of incident peripheral neuropathy (PN). [26] PN is a disorder characterized by damage or dysfunction to peripheral nerves (i.e., nerves outside the brain and spinal cord). It can be caused by ROS accumulation, which compromises peripheral nerves' structural and functional integrity.

Metformin presents another paradox in its mechanism of action. While it promotes anti-aging effects through AMPK activation and reduced ROS flux, long-term exposure could potentially lead to adverse effects rather than benefits. Acting like a throttle on the mitochondria, Metformin can decrease energy production, a factor that becomes particularly relevant in relation to exercise. This impact on mitochondrial function suggests that while Metformin can be beneficial in enhancing metabolic efficiency and reducing oxidative stress, it might simultaneously impair peak muscular performance and recovery by limiting energy availability during and after intense physical activity. This dual effect necessitates a nuanced approach to its use, particularly for those actively engaged in rigorous exercise regimes.

The Connection Between Metformin, Acarbose, and Rapamycin

Rapamycin is considered one of the most potent and well-studied pharmacological interventions for anti-aging. Rapamycin exerts its anti-aging effects by inhibiting the mammalian target of rapamycin (mTOR) pathway.

The mTOR pathway is a central cell growth, proliferation, and metabolism regulator. It includes two main complexes: mTORC1 and mTORC2. mTORC1 is the 'department' that checks if the cell has enough nutrients available, decides when to build more proteins, and when to clean up any waste or damaged components inside the cell via autophagy. Rapamycin, even in small doses, can strongly inhibit the mTORC1 pathway. By modulating this central regulator, Rapamycin can promote cellular processes important for longevity and healthy aging, such as enhanced autophagy, reduced inflammation, and improved cellular resistance. [27]

Acarbose and Metformin are commonly used in tandem with Rapamycin in anti-aging protocols. The common theme among these three compounds is their ability to modulate key cellular pathways and metabolic processes closely linked to aging. Metformin, Acarbose, and Rapamycin have demonstrated promising results in extending lifespan in various animal models by targeting these fundamental mechanisms.

There is some degree of overlap in the mechanisms these three compounds initiate to induce anti-aging effects. Metformin, for instance, has also been reported to inhibit the mTOR pathway, albeit to a lesser extent than Rapamycin. Howell et al. (2017) investigated the effects of Metformin treatment in mice's liver tissue and cells. Through experiments using genetically modified mice, the researchers found that Metformin could inhibit the mTORC1 pathway in the liver even at very low concentrations. Interestingly, this inhibition depended on the AMPK and tuberous sclerosis complex (TSC) protein complex. AMPK, a cellular energy sensor, takes action when Metformin is administered. The TSC complex is a key regulator of the mTORC1 pathway. [28]

Like Metformin, Acarbose also induces anti-aging mechanisms that coincide with Rapamycin's implementation. Both medications operate similarly by acting as calorie restriction (CR) mimetics. Acarbose reduces postprandial glucose spikes and insulin levels. Lowering insulin and glucose levels is a hallmark of CR and has been linked to longevity, as the Arya et al. (2023) study elaborated. [20] On the other hand, Rapamycin inhibits the mTOR pathway. Reduced mTOR signaling is another hallmark of CR. Hence, Acarbose and Rapamycin, through their distinct mechanisms of action, can recapitulate important metabolic and signaling changes during CR.

Metformin, Acarbose, and Rapamycin share commonalities in the key cellular pathways and metabolic processes they target to induce anti-aging effects. This overlap in the fundamental mechanisms—modulation of nutrient-sensing pathways, energy metabolism, and CR-like effects—highlights their potential to work synergistically in promoting healthy aging and lifespan extension.

Comparing Acarbose and Metformin in the Context of Longevity

When considering which compound, Acarbose or Metformin, would be more suitable for promoting longevity, several factors should be considered based on their mechanisms and potential benefits.

Acarbose appears to be a favorable choice for most individuals interested in longevity due to several key reasons:

• Localized Action: Acarbose primarily acts in the gut by inhibiting α-glucosidase enzymes, reducing the digestion of complex carbohydrates into simpler sugars. This localized action means it affects systemic glucose levels less than Metformin, potentially leading to fewer systemic side effects.

• Impact on Gut Microbiome: Beyond glucose regulation, Acarbose has been shown to alter the gut microbiome positively. It promotes the growth of beneficial bacteria like Bifidobacterium and Lactobacillus, which are associated with improved metabolic health, reduced inflammation, and enhanced immune function. A healthy gut microbiome is increasingly recognized as crucial for overall longevity.

On the other hand, Metformin may be more appropriate for individuals specifically dealing with elevated glucose levels or insulin resistance:

• Glucose and Insulin Regulation: Metformin is highly effective in lowering blood glucose levels by reducing liver glucose production and improving insulin sensitivity in peripheral tissues. This makes it particularly beneficial for managing conditions like T2D.

• Potential Side Effects: While both drugs can cause gastrointestinal discomfort and flatulence, Metformin typically has fewer side effects than Acarbose. Metformin also causes greater declines in HbA1c levels over time than Acarbose, making it more suitable for individuals dealing with hyperglycemia. However, the dosage of Metformin needs to be carefully curated, as chronic administration can increase the likelihood of mitochondrial dysfunction, ROS generation, and cellular energy imbalances.

Acarbose and Rapamycin: The Master Combo

For promoting longevity, Acarbose may often be the preferred choice for its localized action and positive effects on the gut microbiome compared to Metformin. 

The most compelling evidence for the combined use of Acarbose with Rapamycin comes from the Interventions Testing Program (ITP). The ITP is a peer-reviewed initiative funded by the National Institute on Aging, aimed at identifying protocols and molecules that extend lifespan and health span. Led by experts in pharmacology, toxicology, and statistical analysis, the ITP began in 2002 and has since identified nine agents that significantly increase lifespan, with Acarbose and Rapamycin being two.

The ITP, under the direction of Strong et al. (2022), conducted an extensive investigation into the combined effects of Acarbose and Rapamycin on lifespan extension in mice. The study aimed to determine if combining these two compounds would provide greater longevity benefits than either drug alone. The researchers bred a cohort of mice and tested several substances, including (R/S)-1,3-butanediol (BD), Captopril (Capt), Leucine (Leu), a botanical mixture called PB125, Sulindac, Syringaresinol, and a combination of Rapamycin (Rapa) and Acarbose (Aca). The substances were administered to different groups of mice starting at either nine months or 16 months of age. Control groups were maintained without any substance intervention to serve as a baseline for comparison.

In male mice, the 'Rapa + Aca' combination starting at nine months significantly extended the lifespan compared to those receiving only Rapamycin. This suggests a synergistic effect that enhances longevity beyond what either compound could achieve alone. In female mice, the lifespan extension with 'Rapa + Aca' was comparable to previous studies with Rapamycin alone, indicating that Acarbose may not provide additional benefits in females. Many other substances tested in this study, including Leucine, PB125, Sulindac, and Syringaresinol, did not show significant lifespan benefits, highlighting the unique effectiveness of the Rapamycin and Acarbose combination [29].

The synergy between Acarbose and Rapamycin can be attributed to their complementary mechanisms. Rapamycin's inhibition of the mTOR pathway mimics the effects of caloric restriction, a well-known intervention for lifespan extension. Acarbose's ability to reduce postprandial glucose and insulin spikes also aligns with caloric restriction mechanisms, promoting metabolic stability and reducing the risk of age-related diseases. Additionally, Acarbose's positive impact on the gut microbiome enhances metabolic health and immune function, creating an environment conducive to longevity. By stabilizing blood glucose levels and improving insulin sensitivity, the combination of Acarbose and Rapamycin addresses key metabolic factors associated with aging [29]. This dual approach ensures a comprehensive strategy for promoting healthy aging.

So why not Metformin? Metformin also targets the mTOR pathway, similar to Rapamycin, albeit to a lesser extent. Additionally, the ITP has not found the same robust longevity benefits from Metformin as from Rapamycin and Acarbose. This raises the question of whether Metformin is necessary if Rapamycin is already being used. Furthermore, as described above, Metformin may limit peak muscular performance and recovery by limiting energy availability during and after intense physical activity. For individuals with vigorous exercise regimens, this may add a further complication. Given that Rapamycin is a more potent inhibitor of mTOR, its use may diminish the need for Metformin when the goal is primarily to target mTOR-related pathways for longevity.

However, if the primary goal of therapy is to improve glucose regulation (particular in the cases of insulin resistance) Metformin may play a crucial role.

The combination of Acarbose and Rapamycin presents a promising strategy for longevity intervention. However, the choice between Acarbose and Metformin should be tailored to individual health needs, considering factors such as glucose regulation, gut microbiome health, and tolerance to potential side effects. Consulting with a healthcare provider is essential to effectively weigh the benefits and risks.

Conclusion

Exploring Rapamycin, Metformin, and Acarbose as longevity interventions offers exciting prospects for extending a healthy lifespan. Rapamycin stands out for its robust research and potent inhibition of the mTOR pathway, which has been shown to enhance autophagy, reduce inflammation, and improve cellular resistance. However, the strategic combination of Rapamycin with other drugs like Acarbose and Metformin presents a potentially more effective approach to promoting longevity.

Acarbose, with its localized action in the gut and positive effects on the gut microbiome, offers a complementary mechanism to Rapamycin's systemic effects. Its ability to reduce postprandial glucose spikes and favorable impact on metabolic stability make it a strong candidate for combination therapy. This synergy is particularly evident in studies showing enhanced lifespan extension when Acarbose is paired with Rapamycin.

On the other hand, Metformin, while also capable of targeting the mTOR pathway to some extent, primarily enhances insulin sensitivity and reduces systemic inflammation. Its role in glucose regulation makes it indispensable for individuals specifically dealing with elevated glucose levels or insulin resistance. However, when used with Rapamycin, its additional benefits on longevity might be less pronounced due to the overlapping mechanisms.

Ultimately, using Acarbose or Metformin combined with Rapamycin should be based on individual health profiles and specific therapeutic goals. For those aiming to optimize gut health and leverage localized metabolic effects, Acarbose may be the superior choice. For individuals requiring robust glucose regulation, Metformin remains a valuable tool.

Looking ahead, integrating these compounds into personalized longevity protocols holds promise for extending a healthy lifespan. Ongoing research and clinical trials will continue to refine our understanding of these drugs' synergistic potential, paving the way for more effective and tailored anti-aging therapies.