Whether you’re brand new to the longevity world or have been working on your health for a while, we think it is very important for anyone curious about longevity to have a solid grasp on the primary building blocks that are currently propelling scientific research forward. Not only will you have a better understanding of what is possible in this field, but we hope this information will help you better orient yourself when exploring options for your longevity protocol.
A great place to start is understanding the hallmarks of aging framework. This new paradigm in the approach to the study of aging is greatly accelerating our understanding of the different processes at play. One element that these aging processes have in common is that they are mediated through some clearly identified molecular / metabolic pathways. The idea of regulating these pathways is a big area of focus of many longevity companies.
We took a deep dive into three key pathways—adenosine monophosphate-activated kinase (AMPK), Sirtuin 1 (SIRT1), and mammalian target of rapamycin (mTOR)—and tried to understand how popular longevity interventions rely on these pathways to produce their anti-aging effects.
This is the summary of what we learned.
Adenosine monophosphate-activated kinase (AMPK) is an enzyme complex that is involved in metabolism. AMPK is composed of three subunits—α, β, and γ—bound together to form a functional enzyme. The β and γ subunits regulate AMPK phosphorylation while the α subunit helps mediate AMPK’s activities as a catalyst. In recent years, AMPK has been implicated as a key signaling molecule in aging because of its roles in cell homeostasis, stress resilience, cell survival and growth, and autophagy.
AMPK is activated by a signal cascade which prompts its activity along three metabolic pathways—glucose, lipids, and mitochondria. When ATP is low inside the cells, the ratio of ADP:AMP increases. Because AMPK is a nutrient sensing enzyme, it activates mechanisms to produce ATP and increase cellular levels; it also inhibits mechanisms that decrease ATP. Along the glucose metabolic pathway, AMPK increases glucose uptake by the cells and promotes glycolysis while simultaneously inhibiting gluconeogenesis and glycogenesis, both of which require ATP. Along the lipid pathway, AMPK increases lipolysis (breakdown of lipids) and β-oxidation while inhibiting lipogenesis and cholesterol synthesis. Finally, when the mitochondrial pathway is in use, AMPK increases mitophagy, autophagy, and cell respiration allowing the cell to perform maintenance and improve mitochondrial efficiency to better produce ATP.
An examination of the research suggests that AMPK signaling has a primary role in the use of longevity supplements, off-label medication use, and exercise for lifespan extension. For example, the diabetes drug metformin is an AMPK activator and has been shown to extend lifespan in mouse models as well as decrease the risk of cancer and other diseases of age. Metformin has also been shown to extend the lifespan of roundworms. In humans, the TAME study was the first to evaluate the use of metformin in delaying age-related diseases in both clinical and observational studies; results from TAME showed that metformin can delay aging and is associated with fewer age-related diseases like Hutchinson-Gilford progeria syndrome (HGPS), Parkinson’s disease, and diabetes. The mechanisms behind the drug’s actions on aging aren’t fully understood yet, but one prominent theory is that metformin acts as a calorie restriction (CR) mimetic. Once inside the cells, metformin activates AMPK by decreasing the ADP/ATP and AMP/ATP levels through the partial inhibition of the electron transport chain inside the mitochondria.
Resveratrol is another longevity compound that has been shown to interact with the AMPK signaling pathway. Resveratrol activates AMPK in response to increase in intracellular calcium and has been shown to reverse mitochondrial dysfunction and oxidative stress in rats. Resveratrol also reduces inflammatory markers like ICAM-1 and TNF-α.
Finally, exercise has also been shown to play a role in exercise-mediated age reversal through the AMPK pathway. For example, this study performed in rats showed that regular aerobic exercise induces autophagy in the hippocampus by mediating AMPK.Along the same lines, this study in female rats showed that HIIT (interval training) upregulates AMPK signaling to improve autophagy and mitochondrial function, reduce oxidative stress, and regulate apoptosis in the skeletal muscles. There has also been compelling evidence to suggest that exercise-induced AMPK activation protects skeletal muscle cells from senescence and that when exercise is coupled with spermidine supplementation, the combination helps to mitigate skeletal muscle atrophy through the AMPK signaling pathway.
Go Deeper: Click here to see a list of ongoing trials examining metformin as an anti-aging agent.
Like AMPK, sirtuins (SIRT) are a family of proteins involved in regulating metabolism. First discovered in the 1970s, sirtuins have since been implicated as key factors for delaying cellular senescence and extending lifespan. There are 7 SIRT isoforms in human biology and Sirtuin 1 (SIRT1) is by far the most widely and well-researched. SIRT1, a NAD+-dependent deacetylase enzyme, is found in the nucleus of the cell where it serves metabolic and epigenetic functions. In heart, liver, fat, and skeletal muscle cells, SIRT1 helps to mediate metabolic functions such as improving ischemic tolerance (ability of cells to resist damaging effects of reduced blood flow) in heart cells, promoting gluconeogenesis sin the liver, increasing fat mobilization in adipose tissue, and promoting the use of fatty acids by skeletal muscles. SIRT1 is also involved in gene silencing (e.g., tumor suppressor p53) and regulating gene transcription and repair.
Sirtuins have shown anti-aging effects in yeast, roundworms, fruit flies, and mice. When it comes to SIRT1, this study found that brain-specific SIRT1-overexpressing (BRASTO) mice have a 9-16% longer lifespan than regular mice. Observed mechanisms suggest that SIRT1 produces its antiaging effects by regulating processes inside the cell such as insulin sensitivity and inflammation. Compounds like resveratrol and ursolic acid, a compound widely found in the peels of apples and other fruits, can also activate SIRT1 directly. Resveratrol specifically has been implicated as a SIRT1 activator in animal models. This study performed in mice showed that long-term resveratrol supplementation improved exercise ability and voluntary motor behavior and reduced negative changes in metabolic signaling via the SIRT1 pathway. Long-term supplementation with resveratrol also delays senescence by regulating the senescence-associated secretory phenotype (SASP), in which cells secrete high levels of inflammatory markers, via SIRT1.
NAD+ has also been shown to play a role in SIRT1 activation, specifically through its precursors nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN). According to this study, NR supplementation in mammalian cells and mice tissues increases NAD+ levels and activates SIRT1 leading to improved metabolism and protection against obesity. Another study suggests that NR can prevent and/or reverse nonalcoholic fatty liver disease via SIRT1. An examination of NMN supplementation suggests that this NAD+ precursor can mitigate age-related physiologic decline, reduce oxidative stress and endothelial dysfunction, and reduce telomere attrition via the SIRT1 pathway.
Exercise is another longevity intervention that interacts with SIRT1. In animal models, sedentary behavior has been shown to reduce SIRT1 activity, while activity, most specifically aerobic exercise, increases SIRT1 activity. According to this study performed in aged rats, treadmill running for a period of 8-weeks enhanced SIRT1 mRNA expression and improved sarcopenia. Exercise has also been shown to reduce systemic inflammation via the SIRT1 pathway (here and here) as well as regulating autophagy by increasing SIRT1 expression.
Go Deeper: Check out this in-depth review of SIRT1 functions in metabolism.
The mammalian target of rapamycin(mTOR) is an enzyme complex that functions as an energy sensor and a regulator for cell growth, metabolism, and aging. mTOR is split into two complexes—mTORC1 and mTORC2—which each serve to regulate different processes inside the cell. mTORC1 is a 5-part protein complex and functions as a nutrient sensor and regulator for protein synthesis. mTORC2 is a 6-part protein complex and functions as a regulator of glucose metabolism, cytoskeleton maintenance, and cell survival.
The mechanism of how mTOR acts as an anti-aging compound isn’t fully understood, although it has been shown to be a key factor in both animal and human models. Based on the research, it appears that the entirety of the enzyme doesn’t aid in longevity; in fact, according to this study, inhibition of mTORC2 has negative effects on health, while inhibition of mTORC1 promotes longevity.
Source: Foster, K. G., & Fingar, D. C. (2010). Mammalian target of rapamycin (mTOR): conducting the cellular signaling symphony. The Journal of biological chemistry, 285(19), 14071–14077. https://doi.org/10.1074/jbc.R109.094003
Examination of common longevity interventions suggests that mTOR has specific interactions with rapamycin (for which the enzyme gets its name), resveratrol, exercise, and calorie restriction. As part of the cohort 2 list of agents in the Interventions Testing Program (ITP), rapamycin was first shown to have longevity effects in 2009. To achieve this, research suggests that rapamycin inhibits mTORC1 by blocking substrate recruitment and restricting access to the enzyme’s active-site while mTROC2 is insensitive to the actions of rapamycin. To date, rapamycin has been shown to reduce aging markers in skin, reverse age-associated arterial dysfunction, protect against neuroinflammation and tau accumulation in the brain, and inhibit senescence in lung cells by its interactions with mTOR.
As with AMPK and SIRT1, resveratrol also interacts with mTOR. In this study performed in rats, resveratrol supplementation upregulated mTROC2 while attenuating the responsiveness of mTORC1. Additionally, exercise affects mTOR activity as well. This study showed that endurance exercise regulates mTOR and prevents age-related narrowing of the renal arteries. In the case of both interventions it appears that the interactions between the therapy and the enzyme pathways are interwoven such that resveratrol and exercise anti-aging effects are dependent on the combined activities of AMPK, SIRT1, and mTOR.
Finally, CR also affects the mTOR pathway. This study performed in fruit flies suggests that CR increases 4E binding protein, a downstream target of mTORC1, and improves mitochondrial activity and lifespan. CR has also been shown to inhibit mTOR in the brain, improving autophagy and reducing the risk for age-related cognitive decline. Other studies suggest that CR protects skeletal muscle mass, prevents the loss of neurons due to age, and inhibits breast cancer tumor growth in mice by either inhibiting or downregulating mTOR.
Go Deeper: Learn more about the regulation and function of mTOR in this review.
Whether you just got started on your health journey or have been at this a while, understanding how popular interventions work at the cellular level can help you decide which ones are worth pursuing and which ones still need to be proven in the lab. Go ahead, do your research and be on your way to a longer, healthier life.
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