Metabolic Regulators: Extending Lifespan by Modulating Energy Production and Mitigating Cell Damage

Metabolic modulators like rapamycin, urolithin A, acarbose, glycine and N-acetyl cysteine, and canagliflozin enhance mitochondrial function to improve metabolism to increase longevity.

(A mitochondria surrounded by a canagliflozin molecule [top left], an acarbose molecule [bottom left], and an N-acetyl cysteine molecule [bottom right])
By Bennett M. Sherman
  1. Rapamycin
    1. Rapamycin’s Modulation of Metabolism
    2. Rapamycin’s Lifespan Extension
  2. Urolithin A
    1. Urolithin A Improves Mitochondria to Enhance Metabolism
  3. Acarbose
    1. Acarbose as a Metabolic Modulator
    2. Acarbose’s Longevity Extension Effects
  4. Glycine and N-Acetyl Cysteine
    1. GlyNAC Modulates Metabolism
    2. GlyNAC’s Influence on Longevity
  5. Canagliflozin
    1. Canagliflozin Enhances Metabolism
    2. Canagliflozin’s Longevity Influences
  6. Supplementing with Metabolic Regulators

Metabolism is the sum of all chemical reactions that take place within cells providing the energy required to synthesize new organic material and drive the function of organs. As we age, metabolic function declines, leading to weight gain and organ deterioration. With this scheme of events in mind, researchers have identified molecules that regulate metabolism. Intriguingly, a number of them even extend mouse lifespan.

Rapamycin’s Modulation of Metabolism

Rapamycin was initially discovered as an antifungal metabolite from the bacteria Streptomyces hygroscopicus found in soil on Easter Island. Rapamycin inhibits a cell protein called mammalian target of rapamycin (mTOR) that plays key roles in metabolic regulation. Together with other proteins such as mammalian lethal with sec-13 protein 8 (mLST8) and regulatory-associated protein of TOR (raptor), mTOR forms a complex called mTORC1. Rapamycin modulates the activation of this protein complex to influence metabolism, protein synthesis, and lipid synthesis to ultimately affect longevity.

(Li et al., 2014 | Cell Metabolism) Cellular pathways influenced by rapamycin and mTORC1 activity include metabolism, protein synthesis, and lipid synthesis.

Metabolically, acute rapamycin treatment has been shown to improve insulin sensitivity. Moreover, rapamycin inhibits the differentiation of fat cells, which may be a way that it helps prevent weight gain. Along those lines, mouse studies have shown that rapamycin treatment protects against high-fat diet-induced obesity in mice. These findings suggest that rapamycin treatments may improve metabolism.

Rapamycin’s Lifespan Extension

Treating mice with 6.72 mg/kg/day of rapamycin for nine months extends male median lifespan by 23% and female median lifespan by 26%. When rapamycin was combined with another metabolic modulator, acarbose, mouse lifespan extensions were even greater. Treating with 2.24 mg/kg/day of rapamycin and 160 mg/kg/day of acarbose for nine months extended male median lifespan by 37% and female median lifespan by 28%. These findings show that modulating metabolism with rapamycin treatment alone or with acarbose treatment substantially extends longevity in mice, providing some optimism that it may help with longevity in humans, also.

Urolithin A Improves Mitochondria to Enhance Metabolism

Urolithin A is a metabolite derived from gut bacteria. Urolithin A’s primary health-enhancing benefit comes from its ability to improve mitochondrial health and function. This molecule has been shown to boost mitochondrial mitophagy — a process whereby the cell disposes of old mitochondria and recycles its protein constituent components — to enhance mitochondrial health. Interestingly, supplementing with 4 mg/kg/day of urolithin A for three months extends male but not female mouse median lifespan by 18.75%. These findings suggest that by enhancing mitochondrial health, urolithin A may provide lifespan extension effects.

Acarbose as a Metabolic Modulator

The complex carbohydrate acarbose is currently FDA approved for treating type 2 diabetes. Taking 50 mg of acarbose three times daily reduces the blood marker for diabetes — hemoglobin A1c — by about 77%.

Although acarbose isn’t FDA approved to treat type I diabetes, 50 mg doses of acarbose administered three times daily for two weeks was found to significantly reduce blood glucose at two hours following meals (postprandial). Another study showed that acarbose significantly decreases low-density lipoprotein (LDL) cholesterol, triglycerides (fats), and total cholesterol compared to another diabetes medicine called metformin. In that study, acarbose also led to a significant reduction in daily insulin usage.

Researchers have also studied acarbose’s abilities to decrease body weight. In a study that included 67,682 diabetes patients, acarbose was found to significantly reduce body weight. Another human trial examining the effects of anti-diabetes drugs on body weight found that acarbose reduced weight by about 3.2%, similar to metformin. These findings point to acarbose’s beneficial effects on metabolism.

Acarbose’s Longevity Extension Effects

Intriguingly, 160 mg/kg/day of acarbose given for four months increased mouse median lifespan. Males showed a 22% median lifespan increase, while females showed a 5% increase in median lifespan. Another study provided similar findings at the same acarbose doses for eight months, showing that acarbose increased male mouse lifespan by 17% and female mouse lifespan by 5%. If these findings apply to humans, acarbose may extend the number of years we live in good health (healthspan).

GlyNAC Modulates Metabolism

The combination of glycine and N-acetyl cysteine (GlyNAC) for supplementation has been found to reverse hallmarks of aging, including the accumulation of unstable, cell-damaging molecules called reactive oxygen species (ROS) and dysfunction of the cell’s powerhouse (mitochondria). GlyNAC functions by boosting a key antioxidant — glutathione.

In a study of older adults between the ages of 61 and 80, 100 mg/kg/day of GlyNAC for 16 weeks improved physical function measured by the distance walked over a six-minute period. As expected, GlyNAC significantly reduced stress (oxidative stress) caused by excessive ROS. GlyNAC also lowered blood markers for DNA damage and reduced blood levels of a protein marker for non-proliferative cells that release inflammatory factors with age (senescent cells). GlyNAC significantly reduced waist circumference and lowered blood pressure when the heart pumps (systolic blood pressure). These findings suggest that GlyNAC supplementation reverses some hallmarks of aging in older adults.

 GlyNAC Enhances Metabolism and Addresses Multiple Aging Hallmarks. The text describes the positive effects of GlyNAC on metabolism and its potential to counter various aspects of the aging process.
(Kumar et al., 2022 | The Journal of Gerontology) GlyNAC improves metabolism and counters multiple hallmarks of aging.

GlyNAC’s Influence on Longevity

GlyNAC supplementation has been shown to increase mouse median lifespan by 24.2% and 23.4% for males and females, respectively. The dosages provided were 1600 mg/kg/day each for both N-acetyl cysteine and glycine. Increasing mouse lifespan with GlyNAC provides some perspective on the possibility that GlyNAC supplementation may counter some hallmarks of aging.

Canagliflozin Enhances Metabolism

Canagliflozin is a medication used against type 2 diabetes. This medication is recommended for use with proper diet and exercise routines to lower blood sugar in adults with type 2 diabetes.

Canagliflozin has been shown to decrease levels of the blood marker for diabetes hemoglobin Hb1c by between 0.77% to 1.16% when given alone or 7.8% to 8.1% when combined with insulin. Canagliflozin has been shown to increase levels of beneficial high-density lipoprotein (HDL) cholesterol but also increases harmful low-density lipoprotein (LDL) cholesterol, thus producing no effect on total cholesterol ratios. Studies have shown that canagliflozin also reduces the risk of heart attack and heart failure for type 2 diabetes patients. These benefits of canagliflozin against diabetes show that the drug positively influences metabolism.

Canagliflozin’s Longevity Influences

Interestingly enough, supplementing mice with 30 mg/kg/day of canagliflozin increases male median lifespan by 14%, while conferring no effect on female mouse lifespan. These findings suggest that canagliflozin may reverse some hallmarks of aging, especially in males.

Supplementing with Metabolic Regulators

Acarbose, GlyNAC, and canagliflozin constitute promising metabolic modulators with evidence showing that they can also extend mouse lifespan. Perhaps the most readily available of these metabolic modulators is GlyNAC, which can be purchased for $399 for 30 to 60 days worth of injections. Alternatively, a month’s worth of GlyNAC capsules are sold for around $35. Since GlyNAC also showed the greatest effects on male and female mouse lifespan, the possibility looms that this combination of glutathione-boosting molecules reverses several hallmarks of aging.

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