Novel Strategies for Healthy Brain Aging

Devin Wahl; Alyssa N. Cavalier; Thomas J. LaRocca


Exerc Sport Sci Rev. 2021;49(2):115-125. 

In This Article

Future Directions: Novel Energy-targeting Strategies for Healthy Brain Aging

Aerobic exercise clearly has a strong, inhibitory influence on all hallmarks of brain aging. Several popular pharmacological candidates for improving healthspan may exert similar effects on certain hallmarks, but most are not as broadly effective as exercise. Of the most commonly studied compounds in the ITP, rapamycin, 17aE, and (to a lesser extent) aspirin seem to be supported by the most encouraging evidence (Figure 3). Of these compounds, rapamycin may be the most promising candidate, as others already have yielded mixed results in clinical settings. Still, clinical data are limited, and further research is needed to determine whether rapamycin or other ITP compounds may be truly effective for inhibiting the hallmarks of brain aging, improving cognitive function, and preventing neurodegenerative diseases in humans.

One key reason that aerobic exercise outperforms common pharmacological healthspan enhancers in the context of brain aging is that exercise provides a strong physiologic/metabolic stimulus. As described above, exercise causes metabolic stress (low cellular energy) linked with accumulation of important energetic signaling molecules (e.g., AMP, NAD+, ketones) (Figures 1 and 4). These and other exercise-induced metabolites flip a "metabolic switch" that activates numerous protective cellular pathways with pleiotropic effects. Interestingly, although anti-aging compounds are not associated with the same hormetic energy stress, a common denominator among the ITP compounds that most favorably modulate hallmarks of brain aging (rapamycin, 17aE, and aspirin) is that they have all been linked with activation of exercise-relevant, energy-sensing pathways. Rapamycin specifically modulates mTOR signaling, and both 17aE and salicylate (the active moiety in aspirin) have been shown to increase signaling/activity of AMPK, SIRT1, and BDNF.[69–71] This observation is consistent with the idea that activation of these energy-sensing pathways is likely required to truly mimic the effects of exercise on the brain. Thus, we hypothesize that several less-studied exercise alternatives that focus on activating energy-sensing pathways may be more effective for healthy brain aging than traditional ITP compounds (Figure 4).

Figure 4.

Exercise is more broadly effective than traditional anti-aging compounds for preserving cognitive function and reducing dementia risk because it is associated with a strong bioenergetic stimulus that directly influences all hallmarks of brain aging. However, some energy-targeting pharmacological agents [e.g., and 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) and nicotinamide riboside (NR)] and lifestyle interventions [e.g., calorie restriction (CR), protein restriction, and intermittent fasting] may better mimic effects of exercise on the hallmarks of brain aging. Potential synergistic effects among these interventions and compounds could hold particular promise for promoting healthy brain aging.

Novel (Non-ITP) Compounds Targeting Energy-sensing Pathways

Many compounds have not been investigated in the ITP but could have powerful effects on brain aging, and those that directly stimulate energy-sensing systems may hold the most promise. Key examples include NAD+-boosting compounds like nicotinamide mononucleotide or nicotinamide riboside (NR; currently under testing in the ITP), 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) or various small molecules that directly activate AMPK (e.g., compound 13, PT-1),[72] as well as metformin (no effect on lifespan in the ITP). There is limited but mostly positive evidence for the effects of these compounds on the brain.[73–75] Future studies will need to determine the bioavailability, ideal dosing, and efficacy of these and other related compounds for healthy brain aging — but given that they directly target exercise-like pathways, this is likely a compelling area for future research.

Novel Dietary/Lifestyle Interventions Targeting Energy-sensing Pathways

Growing evidence suggests that select nutritional interventions (especially those that target energy-sensing pathways) may be similarly/as effective as exercise for healthy brain aging. For example, calorie restriction (CR; 10%–50% reduction in daily caloric intake) and intermittent fasting (IF; periods of time without food) are considered perhaps the strongest nutritional interventions to reduce hallmarks of brain aging.[4] Both CR and IF contribute to hormesis by increasing cellular stress resistance and stress responses,[76] and both have been reported to positively influence the brain and reduce essentially all hallmarks of brain aging.[77,78] The mechanisms underlying CR and IF include powerful modulation of key energy-sensing proteins like AMPK, SIRT1, BDNF, and mTOR.[79] IF and related approaches (e.g., time-restricted feeding[80]), as well as other strategies for mimicking CR (e.g., protein restriction[81]), may be the most practical dietary strategies, as CR is difficult to implement clinically[82] — but the influence of these interventions on human cognitive function/brain aging warrants significant study in the future, as most current evidence is preclinical or limited to peripheral tissues.[83]

Synergistic, Energy-targeted Compound/Intervention Combinations

An interesting direction for future research on strategies for healthy brain aging may be to study similarities/interactions among compounds or interventions. For example, could combinations of compounds targeting energy-sensing pathways more effectively mimic the effects of exercise on the hallmarks of brain aging (i.e., vs. one compound alone)? Or, could exercise, CR, or IF in combination with select compounds have synergistic, protective effects on the aged brain? These ideas are intriguing and could lead to highly translatable strategies for healthy brain aging by reducing the inherent challenges of individual approaches. For instance, a synergistic cocktail of compounds targeting multiple energy-sensing pathways might stimulate greater hormesis (like exercise), and the compounds potentially could be included in lower doses to avoid side effects. Similarly, exercise, CR, or IF could be combined with complementary compounds (i.e., that stimulate similar signaling pathways).

There is conceptual precedent for novel, combinatorial approaches to promote healthy brain aging in other settings. Indeed, the "polypill" concept (combining multiple drugs) is a current and popular research topic in the effort to prevent cardiovascular diseases.[84] End points in any study of an energy pathway–focused polypill for healthy brain aging would be less specific, but focusing on cognitive function and hallmarks of brain aging, as described here, should be a starting point. As for lifestyle intervention/compound synergy, some studies in older adults have pointed to adverse interactions between exercise and otherwise protective compounds like metformin[85] and antioxidants,[86] which may blunt the beneficial hormetic influence of exercise. These reports have focused on peripheral effects of the interventions (e.g., exercise tolerance, performance) rather than brain health, but they suggest a cautionary approach to this area of research. One possible strategy for avoiding these problems might be to combine less intense exercise, or partial CR or IF, with compounds that target complementary energy-sensing pathways. Such interventions could be more manageable for the average adult who might otherwise not adhere, and they would be associated with fewer risks (e.g., injury, malnourishment), which are especially significant concerns among older adults.[82]