Molecular Neuroresilience Biomarkers and the Prediction of Brain Health Across Lifespan

The ability to maintain normal psychological and physical functioning and avoid serious mental illness when exposed to stress and trauma, a phenomenon known as resilience, is a topic that has been investigated over the past several years with increasing attention [1,2]. Recent studies suggest that resilience in humans is not simply the absence of pathological responses that occur in more susceptible individuals, but rather, an active process that adapts over time to stressor conditions [3]. Indeed, mental and physical as well as metabolic stressors are now widely accepted as conditional factors that may compromise an individual’s wellbeing, with broad health implications, including deterioration of mood and cognitive health especially in the aged.

Little is known about these “stressors” as risk factors as a renewed interest in the assessment of resilience has been incorporated in many studies that examine the pathways linking behavioral and social factors to long-term health profiles, including morbidity and mortality. Psychological, physical, and metabolic stressors may mechanistically influence healthy brain aging across the lifespan at a cellular level. The understanding of the molecular mechanisms in the brain as well as peripheral organs is indeed receiving large scrutiny with the long-term goal of developing new preventative interventions to promote healthy brain aging. Certainly, recent progress in the biology of aging research has identified critical “biomarkers” of the aging process, including macromolecular damage or peculiar synaptic “maladaptations” at the basis of the inability to respond to psychological, physical, and metabolic stressors. Most importantly, these investigations are providing unprecedented support for the development and categorization of well-characterized natural compounds that are able to promote neuroresilience at molecular and, eventually, at behavioral levels.

Among the vast class of natural compounds currently under scrutiny for the development of novel “phytodrugs” in preventative strategies to promote healthy brain aging, there are the polyphenols. They have been found to possess a variety of health benefits, including cardiovascular disease risk reduction and protection against neurodegenerative disorders, as well as cancer prevention [4]. In preclinical studies, we found that certain bioavailable, bioactive, and brain-penetrating polyphenol metabolites, particularly those among the flavonoid subclass found from grape sources, effectively promote neuronal plasticity mechanisms that play a major role in learning and memory functions [5, 6]. However, the development of botanical compounds into potential preventative and therapeutic agents is hindered by the fact that most orally consumed polyphenols are extensively metabolized by gastrointestinal epithelial cells during absorption and/or by post-absorptive xenobiotic metabolism [7, 8]. Thus, better understanding of novel multi-targeted pharmacological interventions with novel brain bioavailability, such as polyphenol metabolites and their usage in subjects who are asymptomatic yet who are at high risk for development of neurological and psychiatric disorders, will provide new horizons to promote healthy brain aging. Attempts at the translation of these novel preventative interventions into humans are in their infancy, and there is a dire need to define the parameters that may enhance successful translation into humans.

New emerging studies are challenging the prevailing, and failing approaches of current therapeutic intervention with current available treatments in neuropsychiatric disorders. It is therefore not surprising that just in the last few years we have witnessed an increase in the consumption of natural compounds for integrative treatment of mental illnesses. In the meantime, new rigorous scientific investigations are teasing apart new molecular pathways and novel molecular targets for certain botanical supplements. Through this characterization and “repurposing” of select natural products that are able to attenuate maladaptive molecular mechanisms in the brain over a lifespan, we will undoubtedly devise new preventative approaches to define drug-like properties while identifying novel target derivations of select bioactive metabolites coming from complex botanicals to promote healthy brain aging [9]. We want to point out that for the development of feasible translational human studies, interventions need to be introduced during midlife or earlier, and in the absence of disease. For this reason, new efforts are currently directed toward research of surrogate “biomarkers of neuroresilience” that can be used in experimental model systems or clinical settings that are shorter in duration than a full lifespan, or even shorter than the time from midlife to death. Shedding light on mechanisms associated with neuroresilience and characterization of novel molecular biomarkers of brain resilience will provide surrogate molecular fingerprints predictive of future brain health.

The new interest in select cellular mechanisms is key to the understanding of how well-characterized brain bioavailable bioactive polyphenol metabolites may contribute to local brain network activities and overall healthy brain functioning. For example, in vivo optogenetic investigation combined with behavioral and epigenetic modification in the same experimental model in response to stressful experimental conditions over time will undoubtedly provide new tools in the refinement of highly characterized bioactive polyphenol metabolites to mitigate “maladaptation” of select neural populations even decades before onset of symptomatic brain degenerative disorders.

Collectively, we hypothesize that better characterization of phenotypic responsiveness to “stressors” will provide novel measures of brain resilience which will for the first time provide novel correlates able to instruct us on short-term health risks. Undoubtedly, stressful conditions in experimental models of “psychological and cognitive resilience” will provide an unprecedented “springboard” for characterizing integrative pharmacological interventions to improve “health span” while attenuating age-related brain morbidity. We are excited by this new challenge; If we will succeed in the characterization of interventions that increase brain and mental health based on modification of one or more of the major “biomarkers” of neuroresilience (molecular surrogate of successful brain aging), we might one day be able to promote resilience pharmacologically, possibly through preventative treatment with novel and safe “phytodrugs” against psychological [10], physical, and metabolic stressors, and possibly predict future brain health across the lifespan.

Collectively more mechanistic investigations directed toward the understanding maladaptive molecular mechanisms in the brain during one’s lifespan to promote resilience as well as better characterization of genetic risk for age-related cognitive deterioration, independent from classical dementia neuropathology, in normal individuals [11] will provide an unprecedented opportunity to devise new preventative approaches in promoting healthy brain aging in normal but yet susceptible subjects.

Giulio Maria Pasinetti, Breanna Valcarcel, Libby Ward, Tal Frolinger, Chad Smith, Lap Ho, Jun Wang
Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY and Geriatric Research, Education & Clinical Center, James J. Peters Veterans Affairs Medical Center, Bronx, NY, USA

Questions for Discussion

  • How do new vulnerabilities or strengths with respect to age-related cognitive abilities emerge over the life course?
  • What pathways predict brain resilience despite multiple risk factors in aging?
  • How can research findings on neuronal plasticity and lifestyle preventable risk factors, e.g., psychological stress and mood disorder, brain injury, type II diabetes, etc., be used to help individuals thrive in spite of chronic disease?
  • How might we translate research findings on molecular neuroresilience and investigations of genetic risk to improve our ability detect at-risk individuals across early life into evidence-based health interventions and eventually technological advances?
  • How can known life-long preventative interventions be translated into programs, policies, etc, that might sustain resilience over one’s lifespan?

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[2] Kimhi S (2016) Levels of resilience: Associations among individual, community, and national resilience. J Health Psychol 21, 164–170.
[3] Russo SJ, Murrough JW, Han MH, Charney DS, Nestler EJ (2012) Neurobiology of resilience. Nat Neurosci 15, 1475–1484.
[4] Chen AY, Chen YC (2013). A review of the dietary flavonoid, kaempferol on human health and cancer chemoprevention. Food Chem 138, 2099–2107.
[5] Ho L, Ferruzzi MG, Janle EM, Wang J, Gong B, Chen TY, Lobo J, Cooper B, Wu QL, Talcott ST, Percival SS, Simon JE, Pasinetti GM (2013) Identification of brain-targeted bioactive dietary quercetin-3-O-glucuronide as a novel intervention for Alzheimer’s disease. FASEB J 27, 769–781.
[6] Wang J, Ferruzzi MG, Ho L, Blount J, Janle EM, Gong B, Pan Y, Gowda GA, Raftery D, Arrieta-Cruz I, Sharma V, Cooper B, Lobo J, Simon JE, Zhang C, Cheng A, Qian X, Ono K, Teplow DB, Pavlides C, Dixon RA, Pasinetti GM (2012) Brain-targeted proanthocyanidin metabolites for Alzheimer’s disease treatment. J Neurosci 32, 5144–5150.
[7] Gao S, Hu M (2010) Bioavailability challenges associated with development of anti-cancer phenolics. Mini Rev Med Chem 10, 550-567.
[8] Monagas M, Urpi-Sarda M, Sánchez-Patán F, Llorach R, Garrido I, Gómez-Cordovés C, Andres-Lacueva C, Bartolomé B (2010) Insights into the metabolism and microbial biotransformation of dietary flavan-3-ols and the bioactivity of their metabolites. Food Funct 1, 233–253.
[9] Qureshi NA, Al-Bedah AM (2013) Mood disorders and complementary and alternative medicine: A literature review. Neuropsychiatr Dis Treat 9, 639–658.
[10] Ward L, Pasinetti GM (2016) Recommendations for development of botanical polyphenols as ‘‘natural drugs’’ for promotion of resilience against stress-induced depression and cognitive impairment. Neuromolecular Med, doi: 10.1007/s12017-016-8418-6.
[11] Mormino EC, Sperling RA, Holmes AJ, Buckner RL, De Jager PL, Smoller JW, Sabuncu MR; Alzheimer's Disease Neuroimaging Initiative (2016) Polygenic risk of Alzheimer disease is associated with early-and late-life processes. Neurology 87, 10-1212.

Last comment on 5 August 2016 by Heather Snyder, Ph.D.


Pasinetti et al. launch a discussion on stressors and neuroresilience—particularly with regard to prevention and treatment of CNS diseases across the lifespan. What are the molecular mechanisms of neuroresilience, and can we identify druggable targets in these pathways? Polyphenols may represent the first generation of such treatments, but we need novel compounds with more favorable pharmacokinetics and thus greater efficacy.

Aging in the most important risk factor for Alzheimer’s disease (AD) and other neurodegenerative disorders, and aging alone is a major stressor. Genetics, particularly the ApoE genotype, is also an important factor in AD susceptibility and resilience. While molecular mechanisms remain unclear, aging and the ApoE4 genotype converge in promoting CNS Aβ/amyloid accumulation and deposition—thus introducing a third stressor. Diabetes mellitus, traumatic brain injury, and other stressors may also collude to induce first mild cognitive impairment (MCI) and then progressive dementia due to AD.

How can we prevent or break these vicious cycles? Factors that may delay or prevent MCI and AD, and thus promote resilience, include lifelong education, physical exercise, mental and social engagement, and consuming a Mediterranean diet—pointing to molecular mechanisms that may also be exploited pharmacologically. Hormesis is defined as the effect of a small stressor in promoting resilience against a subsequent stressor—or “That which doesn’t kill me, makes me stronger” (Friedrich Neitzsche). For example, caloric restriction (consuming only 2/3 normal calories) is a stressor that delays or prevents diseases of aging, including neurodegenerative disorders, although the evidence is mostly preclinical. Caloric restriction may involve a group of genes/deacetylases called sirtuins that are regulated by cellular energy balance (NAD+/NADH) to alter gene transcription. Sirtuins may be the, or perhaps a, molecular target of polyphenols. However, there are likely many pathways to increased resilience.

We tested the hypothesis that treatment with the polyphenol resveratrol may be beneficial to subjects with mild to moderate AD [1]. We cited abundant preclinical evidence of Pasinetti et al. and other investigators in suggesting that resveratrol mimics the effects of caloric restriction in promoting resilience. The study of mild-moderate AD subjects demonstrated that resveratrol stabilized CSF Aβ40 levels over the 12-month treatment period, as well as CSF Aβ42 levels in the subset of individuals with biomarker-confirmed AD. In addition, activities of daily living declined less in the resveratrol-treated group (compared to placebo), even though the phase 2 trial (N=119) was underpowered to detect a change in clinical outcomes. Oral dosage of up to 1 g pure synthetic resveratrol twice daily was safe and tolerable. Despite the high dosage, levels of unmodified resveratrol in CSF (and brain?) reached only low nM levels, suggesting a high-affinity molecular target, and high potency. More recent data also suggest a potent anti-inflammatory effect of resveratrol—for example, in reducing CSF matrix metalloproteinase 9 levels by ~50% [2]. Collectively, these data suggest that polyphenols may be a safe and effective strategy for the prevention and treatment of MCI and AD by engaging resilience pathways.

After all non-drug strategies are implemented to promote resilience, pharmacologic strategies—for individuals at high risk or those already diagnosed—will remain essential. The first generation of AD drugs, available now, are neurotransmitter-based, and provide only modest, temporary, and palliative benefits (not disease-modifying). If the amyloid hypothesis of AD is correct, the second generation of AD drugs may be anti-amyloid strategies. Perhaps the next generation of treatments for neurodegenerative disorders will be based on molecular mechanisms and targets promoting neuroresilience, with polyphenols opening the door to new possibilities.

R. Scott Turner, MD, PhD and Charbel Moussa, MD, PhD

[1] Turner RS, Thomas RG, Craft S, vanDyck CH, Mintzer J, Brewer JB, Rissman RA, Raman R, Aisen PS (2015) A randomized, double-blind, placebo-controlled trial of resveratrol for Alzheimer disease. Neurology 85, 1383-1391.
[2] Moussa C, Hebron M, Huang X, Brown H, Rissman R, Aisen P, Turner RS (2016) Resveratrol activates the CNS Sirtuin1/Matrix Metalloproteinase-9 pathway and regulates neuroinflammation in Alzheimer’s disease. Alzheimer’s Association International Conference 2016, Toronto, Canada (Abstract O4-08-04).

Alzheimer’s disease is growing at an alarming rate in the United States and around the world. Today, more than 47 million people are living with Alzheimer’s or another dementia worldwide, and that number is expected to double in the next 20 years, and triple by 2050 [1]. There is a desperate need for interventions to stop or slow the progression of disease. As the leading voluntary health organization dedicated to Alzheimer’s disease, the Association is an adamant supporter of all legitimate avenues of scientific investigation—from basic research into the causes of the disease through clinical trials. There is a need to increase the pipeline of potential treatments/ prevention strategies for Alzheimer’s and related dementia. The Alzheimer’s Association Part the Cloud Translational Research Program has invested resources into advancing clinical trials examining alternative energy sources for the brain as possible avenue of therapeutic intervention. One of these awards includes Dr. Pasinetti’s trial examining the potential therapeutic benefit of polyphenols in individuals with mild cognitive impairment to assess the safety, side effects and optimal dosing of their polyphenol preparation [2].

Central to the development of future potential therapeutic strategies is the need to understand successful aging and potential lifestyle or combination interventions that will benefit overall brain health. A key theme emerging from this year’s Alzheimer’s Association International Conference (AAIC) in Toronto focused on the issue of resilience, and specifically the role of cognitive reserve. Dr. Pasinetti’s article discusses the “critical” nature of identifying these “biomarkers of the aging process, including macromolecular damage or peculiar synaptic 'maladaptations' at the basis of the inability to respond to psychological, physical and metabolic stressors.” The Alzheimer’s Association suggests that we can also evaluate successful aging to elucidate the underpinnings of the biological process in aging and in disease. Through linking both the knowledge of these “stressors” and of strategies for successful aging, the field can develop and implement strategies to incorporate for future combination approaches of lifestyle and/or medications.

Further, by examining the biological stressors and the underlying mechanistic contributions of these to disease, there may be alternative avenues for therapeutic development. For instance, the Alzheimer’s Association has led recent discussions focusing on vascular contributions to cognitive impairment and Alzheimer’s to elucidate the strong linkage between mechanism pathways and biologic processes [3]. As such, there is a growing emphasis on establishing biological measures of change and incorporating these measures for clinical trial evaluation.

Similarly there is a need to develop strategies of new molecular pathways and targets for discovery, including the potential for natural compounds as a component of the integrative treatment approach, or as a part of the combination for therapeutic intervention in Alzheimer’s disease and related dementia. For instance, Turner and colleagues, in collaboration with the Alzheimer’s Disease Cooperative Study, recently reported on the safety and tolerability of a resveratrol (500 mg or 1000 mg) in a placebo-controlled phase II, 52 week multi-center with mild to moderate Alzheimer’s [4]. Resveratrol is a natural substance derived from plants, and is found in red wine and the skin of red grapes; the dosage tested in this trial was a formulation far exceeding its natural occurrence in either of those foods/ drinks [5]. There are other such ongoing initiatives to properly engage in the scientific rigor of investigation to determine the potential efficacy and safety of natural compounds.

Growing evidence suggests the field should also consider combining these strategies of pharmacologic (medical or natural products), with lifestyle changes. In 2014, the Finnish Geriatric Intervention Trial (FINGER Trial) presented findings at the AAIC suggesting that after two years in a cognitively healthy population of a specific multimodal lifestyle intervention that they were able to delay cognitive decline compared to standard of care control. Building on this trial as well as many other studies, the Alzheimer’s Association evaluated the strength of the scientific evidence around modifiable risk factors as linked to cognitive decline and/or dementia. As a result of this review, the Alzheimer’s Association states that there is sufficiently strong evidence, from a population perspective, to conclude that regular physical activity, management of cardiovascular risk factors and specific targeted cognitive training reduce the risk of cognitive decline and may reduce the risk of dementia. The Association further believes that there is sufficiently strong evidence to conclude that a healthy diet may also reduce the risk of cognitive decline [6, 7].

[1] Alzheimer’s Disease International 2015 Report
[2], last accessed August 4, 2016.
[3] Snyder HM, Corriveau RA, Craft S, Faber JE, Greenberg SM, Knopman D, Lamb BT, Montine TJ, Nedergaard M, Schaffer CB, Schneider JA, Wellington C, Wilcock DM, Zipfel GJ, Zlokovic B, Bain LJ, Bosetti F, Galis ZS, Koroshetz W, Carrillo MC (2014) Vascular contributions to cognitive impairment and dementia including Alzheimer’s disease. Alzheimers Dement 11, 710-717.
[4] Turner RS, Thomas RG, Craft S, van Dyck CH, Mintzer J, Reynolds BA, Brewer JB, Rissman RA, Raman R, Aisen PS; Alzheimer's Disease Cooperative Study (2015) A randomized, double-blind, placebo controlled trial of resveratrol for Alzheimer’s disease. Neurology 85, 1383-1391.
[5], last accessed August 2, 2016.
[6] Baumgart M, Snyder HM, Carrillo CM, Fazio S, Hye K, Johns H (2015) Summary of the evidence on modifiable risk factors for cognitive decline and dementia: A population-based perspective. Alzheimers Dement 11, 718-726.
[7] Edwards J, University of South Florida (2016) The ACTIVE Study: What We Have Learned and What Is Next? Alzheimer’s Association International Conference, 2016.