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This paper addresses how long lifespan can be extended via multiple interventions, such as dietary supplements [e.g., curcumin, resveratrol, sulforaphane, complex phytochemical mixtures (e.g., Moringa, Rhodiola)], pharmaceutical agents (e.g., metformin), caloric restriction, intermittent fasting, exercise and other activities. This evaluation was framed within the context of hormesis, a biphasic dose response with specific quantitative features describing the limits of biological/phenotypic plasticity for integrative biological endpoints (e.g., cell proliferation, memory, fecundity, growth, tissue repair, stem cell population expansion/differentiation, longevity). Evaluation of several hundred lifespan extending agents using yeast, nematode (Caenorhabditis elegans), multiple insect and other invertebrate and vertebrate models (e.g., fish, rodents), revealed they responded in a manner [average (mean/median) and maximum lifespans] consistent with the quantitative features [i.e., 30-60% greater at maximum (Hormesis Rule)] of the hormetic dose response. These lifespan extension features were independent of biological model, inducing agent, endpoints measured and mechanism. These findings indicate that hormesis describes the capacity to extend life via numerous agents and activities and that the magnitude of lifespan extension is modest, in the percentage, not fold, range. These findings have important implications for human aging, genetic diseases/environmental stresses and lifespan extension, as well as public health practices and long-term societal resource planning., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The present paper identifies a critical factor that leads to false negative results (i.e., failing to indicate efficacy when beneficial results did occur) in randomized human drug trials. The paper demonstrates that human performance can only be enhanced by a maximum of 30-60% as described by the hormetic dose response which defines the limits of biological plasticity. However, human epidemiological/clinical trials typically contain such extensive variability that often requires responses greater than 2-3 times control group responses to show statistical significance. Thus, many potentially beneficial agents may be missed because the clinical trial fails to recognize and take into consideration the limits of biological plasticity. The paper proposes that this hormesis-biological plasticity-clinical trial conundrum can be addressed successfully via the use of a weight-of-evidence methodology similar to that used by regulatory agencies such as EPA in environmental assessment of chemical toxicity., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. G. Dhawan is employed by Stantec (ChemRisk), a consulting firm that provides scientific support to the government, corporations, law firms, and various scientific/professional organizations., (Copyright © 2023 Elsevier B.V. All rights reserved.)

This paper represents the first assessment of hormetic dose responses by human dental pulp stem cells (hDPSCs) with particular emphasis on cell renewal (proliferation) and differentiation. Hormetic dose responses were commonly reported in this model, encompassing a broad range of chemicals, including principally pharmaceuticals (e.g., metformin and artemisinin), dietary supplements/extracts from medicinal plants (e.g., berberine, N-acetyl-L-cysteine, and ginsenoside Rg1) and endogenous agents (e.g., ATP, TNF-α). The paper assesses mechanistic foundations of the hDPSCs hormetic dose responses for both cell proliferation and cell differentiation, study design considerations, and therapeutic implications., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The present paper demonstrates that metformin (MF) induced a broad spectrum of hormetic biphasic dose responses in a wide range of experimental studies, affecting multiple organ systems, cell types, and endpoints enhancing resilience to chemical stresses in preconditioning and co-current exposure protocols. Detailed mechanistic evaluations indicate that MF-induced hormetic-adaptive responses are mediated often via the activation of adenosine monophosphate-activated kinase (AMPK) protein and its subsequent upregulation of nuclear factor erythroid 2-related factor 2 (Nrf2). Hormesis-induced protective responses by MF are largely mediated via a vast and highly integrated anti-inflammatory molecular network that enhances longevity and delays the onset and slows the progression of neurodegenerative and other chronic diseases., (Copyright © 2021 Elsevier B.V. All rights reserved.)

This paper provides evidence to support that riluzole, an FDA-approved treatment for amyotrophic lateral sclerosis (ALS), like many neuroprotective agents, displays and exerts hormetic biphasic dose responses. These findings have important implications for the experimental study and clinical treatment of ALS., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Ginkgo biloba (GB) extracts have been shown to commonly induce biphasic dose responses in a range of cell types and endpoints (e.g., cochlea neural stem cells, cell viability, cell proliferation). The magnitude and width of the low dose stimulation of these biphasic dose responses are similar to those reported for hormetic dose responses. These hormetic dose responses occur within direct stimulatory responses as well as in preconditioning experimental protocols, displaying acquired resistance within an adaptive homeodynamic and temporal framework and repeated measurement protocols. The demonstrated GB dose responses further reflect the general occurrence of hormetic dose responses that consistently appear to be independent of the biological model, endpoint, inducing agent, and/or mechanism. These findings have important implications for consideration(s) of study designs involving dose selection, dose spacing, sample size, and statistical power. This illustrates and strengthens the need to characterize the low dose stimulatory response range and optimal dose in order to explore potential public health and clinical applications of plant-derived agents, such as GB., (Copyright © 2020. Published by Elsevier B.V.)

The global increases in life expectancy and population have resulted in a growing ageing population and with it a growing number of people living with age-related neurodegenerative conditions and dementia, shifting focus towards methods of prevention, with lifestyle approaches such as nutrition representing a promising avenue for further development. This overview summarises the main themes discussed during the 3 rd Symposium on "Nutrition for the Ageing Brain: Moving Towards Clinical Applications" held in Madrid in August 2018, enlarged with the current state of knowledge on how nutrition influences healthy ageing and gives recommendations regarding how the critical field of nutrition and neurodegeneration research should move forward into the future. Specific nutrients are discussed as well as the impact of multi-nutrient and whole diet approaches, showing particular promise to combatting the growing burden of age-related cognitive decline. The emergence of new avenues for exploring the role of diet in healthy ageing, such as the impact of the gut microbiome and development of new techniques (imaging measures of brain metabolism, metabolomics, biomarkers) are enabling researchers to approach finding answers to these questions. But the translation of these findings into clinical and public health contexts remains an obstacle due to significant shortcomings in nutrition research or pressure on the scientific community to communicate recommendations to the general public in a convincing and accessible way. Some promising programs exist but further investigation to improve our understanding of the mechanisms by which nutrition can improve brain health across the human lifespan is still required., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Ageing is a highly complex process marked by a temporal cascade of events, which promote alterations in the normal functioning of an individual organism. The triggers of normal brain ageing are not well understood, even less so the factors which initiate and steer the neuronal degeneration, which underpin disorders such as dementia. A wealth of data on how nutrients and diets may support cognitive function and preserve brain health are available, yet the molecular mechanisms underlying their biological action in both normal ageing, age-related cognitive decline, and in the development of neurodegenerative disorders have not been clearly elucidated., Objectives: This review aims to summarise the current state of knowledge of vulnerabilities that predispose towards dysfunctional brain ageing, highlight potential protective mechanisms, and discuss dietary interventions that may be used as therapies. A special focus of this paper is on the impact of nutrition on neuroprotection and the underlying molecular mechanisms, and this focus reflects the discussions held during the 2nd workshop 'Nutrition for the Ageing Brain: Functional Aspects and Mechanisms' in Copenhagen in June 2016. The present review is the most recent in a series produced by the Nutrition and Mental Performance Task Force under the auspice of the International Life Sciences Institute Europe (ILSI Europe)., Conclusion: Coupling studies of cognitive ageing with studies investigating the effect of nutrition and dietary interventions as strategies targeting specific mechanisms, such as neurogenesis, protein clearance, inflammation, and non-coding and microRNAs is of high value. Future research on the impact of nutrition on cognitive ageing will need to adopt a longitudinal approach and multimodal nutritional interventions will likely need to be imposed in early-life to observe significant impact in older age., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)