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

ITP Alternatives to Aerobic Exercise for Healthy Brain Aging

Aerobic exercise is perhaps the best way to protect brain health during aging, but it may not be feasible for some people. In addition, in Western societies where sedentary lifestyles have become common, many may find it difficult to exercise regularly. It is therefore an opportune time to consider whether anti-aging compounds may recapitulate some benefits of exercise on the brain. The National Institute on Aging's ITP has tested the effects of many compounds on healthspan and lifespan in genetically heterogeneous mice. To date, a number of compounds tested by the ITP have been shown to improve health, increase lifespan, and reduce many hallmarks of aging in vitro and in vivo. The six ITP compounds that are the most heavily studied include aspirin, rapamycin, 17-α-estradiol (17aE), acarbose, nordihydroguaiaretic acid (NDGA), and Protandim. All of these compounds elicit beneficial health responses in peripheral tissues. Thus, these pharmacological interventions may also improve brain health[44] and reduce some hallmarks of brain aging (Figure 3). As these are among the most-studied pharmacological anti-aging interventions, comparing the evidence for the effects of these ITP compounds with those of exercise on the brain may provide insight on key mechanisms/targets for healthy brain aging.

Figure 3.

Select pharmacological "anti-aging" treatments that have been shown to increase lifespan/healthspan in the National Institute on Aging's Intervention Testing Program (ITP) may inhibit certain hallmarks of brain aging, but some are supported by more evidence than others. To date, rapamycin and 17aE seem to be the most effective in this context. However, more research is needed to determine how these and other compounds affect additional hallmarks of brain aging and to fully characterize bioavailability and safety in humans.


Aspirin may enhance health/lifespan both by suppressing inflammation and through its antioxidant properties.[44] Evidence suggests that aspirin supplementation improves brain health during aging by reducing oxidative stress and inflammation and by protecting against neurotoxic stressors in dopaminergic neurons (which are important for learning and memory) via enhanced mitochondrial function and reduced ROS production.[45] In addition, aspirin improves lysosomal biogenesis and autophagy and reduces plaque pathology in transgenic AD mice.[46] Aspirin treatment also reduces stress sensitivity in mice by lowering the activity of the hypothalamic-pituitary-adrenal stress axis and decreasing the expression of GFAP (a marker of proinflammatory astrocytes).[47] Finally, both low-dose and high-dose aspirin supplementation improve neurogenesis by increasing oligodendrocyte proliferation and white matter integrity in rats.[48]

In humans, there is mixed evidence that aspirin supplementation in older age may protect against cognitive decline. For example, low-dose aspirin intake is associated with higher scores on cognitive tests in older adults in some studies; however, some meta-analyses have found no association between low-dose aspirin supplementation and improved cognitive health or protection against dementia in older adults.[49] Other promising anti-inflammatories currently under investigation for healthy aging/brain aging in humans include salsalate and naproxen.[50]


Rapamycin inhibits intracellular growth cascades (largely by inhibiting mTOR), and it increases median and maximal lifespan in male and female mice.[6] There is evidence that rapamycin influences most hallmarks of aging in peripheral tissues and growing support for similar effects in the brain. For example, rapamycin reduces oxidative stress in the brains of old rats by activating autophagy, decreasing neuroinflammation, and improving neuronal integrity.[51] Acute injection of rapamycin also reduces proinflammatory cytokines and chemokines and inhibits the activity of macrophages and microglia.[4]

Research on rapamycin and the brain is evolving, and the compound may reduce some markers of brain aging via recently discovered mechanisms. For example, rapamycin supplementation is reported to influence the expression of brain telomerase reverse transcriptase (TERT), which maintains telomere integrity and reduces ROS.[52] Chronic rapamycin supplementation also improves NMDA (a glutamate and ion channel receptor that plays a role in synaptic plasticity) signaling. In addition, rapamycin suppresses senescence in rat models of accelerated aging and improves myelination and neuronal structure.[53] Long-term rapamycin supplementation even enhances vasculature and brain/neuronal metabolism in mouse models of AD.[54] To date, there have been no clinical trials investigating the influence of rapamycin on the hallmarks of brain aging. However, some argue that such trials should soon occur because of the large number of positive results in animal models. There also is a current phase 1b/2a trial underway to determine whether mTOR inhibition with the novel compound RTB101 may benefit patients with PD (ACTRN12619000372189).


17aE is an endogenous steroid with an affinity for estrogen receptors. Long-term treatment with 17aE increases median lifespan in male mice but not females.[6] Interestingly, the brain has many estrogen receptors (which decline in number during aging), and it has therefore been suggested that 17aE might reduce hallmarks of brain aging. Estrogen also modulates neuron-to-neuron communication, helps in the production of brain growth factors, and has a supportive role for glial cells. In fact, 17aE has been shown to reduce age-associated hypothalamic inflammation, in part by diminishing the activity of reactive/proinflammatory microglia and suppressing TNF-α and GFAP (i.e., astrocyte activation).[55] Other reports show that 17aE protects against intraneuronal ROS production and reduces markers of oxidative stress in the brain.[56]

There also is evidence that estrogen may improve neuronal calcium homeostasis by suppressing intracellular calcium accumulation, reduce DNA damage in the brain, and stimulate neurogenesis in the hippocampus. Moreover, it has been shown that estradiol can have a direct impact on neuronal network activity by stimulating synaptic excitatory activity, enhancing calcium dynamics, and improving neuronal structure.[57] 17aE may even reduce amyloid beta-induced neuronal cell death (a feature of AD), in part by enhancing mitochondrial function.[56]

Although preclinical evidence in favor of 17aE is promising, existing data in humans are less clear. Studies on postmenopausal women given hormone replacement therapy have documented a mild association with self-reported estrogen supplementation and reduced risk of dementia.[58] However, others have reported that long-term 17-β-estradiol (an isomer of 17aE) does not influence verbal memory, executive function, or global cognitive ability.[59] Thus, more studies are needed to determine whether estrogen or related hormones may influence cognitive function or dementia in larger cohorts and whether these compounds may do so by modulating hallmarks of brain aging.


Acarbose is an inhibitor of small intestinal α-glucosidase that prevents the breakdown of complex carbohydrates into glucose, resulting in decreased glucose absorption and lower blood glucose levels. Acarbose increased median lifespan in the ITP, but the effect was greater in male mice.[6] One recent study has shown that chronic acarbose treatment improves synaptic integrity and increases the expression of NGFs, which coincides with improved memory in a mouse model of accelerated aging.[60] Acarbose also decreases age-associated hypothalamic inflammation in male mice but not females.[55] One population-based retrospective cohort study showed that acarbose use is associated with a reduced risk of dementia in persons with type 2; however, this effect was seen only in women.[61]

Nordihydroguaiaretic Acid

NDGA, an antioxidant compound found in the creosote bush, has reported anti-inflammatory and antioxidant capabilities. NDGA improved median lifespan in the ITP, but only in male mice.[6] There is limited evidence that NDGA may protect against several hallmarks of brain aging in rodents. For example, NDGA supplementation is associated with reduced age-related hypothalamic inflammation and glial cell reactivity in old mice.[55] In addition, NDGA improves mitochondrial function, membrane potential, ATP generation and morphology, and synaptic structure in the striatum of mice. These positive changes are associated with reduced lipid peroxidation and attenuated oxidative stress.[62] Finally, NDGA protects cerebellar neurons against H2O2-induced oxidative stress by activating Nrf2 antioxidant pathways.[63] Despite these few studies suggesting that NDGA may be protective against brain aging and neurodegenerative diseases in animal models, there have been no studies investigating the influence of this compound on brain aging in humans.


Protandim is a mixture of five botanical compounds (curcumin, bacosides, silymarin, withaferin A, and epigallocatechin-3-gallate). It is an Nrf2 activator and may benefit health by increasing endogenous antioxidant activity. In the ITP, Protandim improved median lifespan, but the effect was only seen in male mice.[6] Many studies have investigated the benefits of Nrf2 activation in brain aging and neurodegenerative diseases; however, only a few have specifically looked at the effects of Protandim supplementation on the brain. A recent study showed that Protandim reduces oxidative stress and mitochondrial oxidizing species in rat brains,[64] but further studies are needed to determine the effects of Protandim on other hallmarks of brain aging. There also is some interest in additional/novel Nrf2 activators, such as sulforaphane and dimethyl fumarate, and these may have promise in this context.


Several other promising compounds and phytochemicals (some currently being tested in the ITP) may have the ability to influence the hallmarks of brain aging. Although not described in detail in the current review, these compounds include the polyphenol resveratrol,[65] senolytic compounds (which clear senescent cells),[66] curcumin (derived from the Indian spice turmeric),[67] and spermidine (an autophagy activator).[68] Most of these compounds have been shown to influence some hallmarks of brain aging and are well tolerated in humans. These compounds, in addition to those described, may have great potential to positively influence brain health during aging and reduce the risk for neurodegenerative disease. However, more rigorous research is needed to determine effective doses, bioavailability, and mechanisms of action before clinical trials commence.