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 . 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 . 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 . 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 , 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  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?
References  Aburn G, Gott M, Hoare K (2016) What is resilience? An integrative review of the empirical literature. J Adv Nurs72, 980–1000.  Kimhi S (2016) Levels of resilience: Associations among individual, community, and national resilience. J Health Psychol21, 164–170.  Russo SJ, Murrough JW, Han MH, Charney DS, Nestler EJ (2012) Neurobiology of resilience. Nat Neurosci15, 1475–1484.  Chen AY, Chen YC (2013). A review of the dietary flavonoid, kaempferol on human health and cancer chemoprevention. Food Chem138, 2099–2107.  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 J27, 769–781.  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 Neurosci32, 5144–5150.  Gao S, Hu M (2010) Bioavailability challenges associated with development of anti-cancer phenolics. Mini Rev Med Chem10, 550-567.  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 Funct1, 233–253.  Qureshi NA, Al-Bedah AM (2013) Mood disorders and complementary and alternative medicine: A literature review. Neuropsychiatr Dis Treat9, 639–658.  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.  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. Neurology87, 10-1212.