Decline in biological resilience as key manifestation of aging: Potential mechanisms and role in health and longevity

Interactions Between Genes From Aging Pathways May Influence Human Lifespan and Improve Animal to Human Translation

“…To explore the possibility that genes from the major aging pathways (IGF1/AKT/FOXO3, TP53/P21/P16, and mTOR/S6K mediated) may influence human lifespan as result of their interplay rather than independently, we selected the set of candidate genes ( Table 1B ) that belong to these pathways and have also been featured in aging research, as genes or their products ( Braeckman and Vanfleteren, 2007 ; Feng et al, 2007 ; Tsai et al, 2008 ; Ghosh et al, 2010 ; Kenyon, 2010 ; Johnson et al, 2013 ; Nojima et al, 2013 ; Ortega-Molina and Serrano, 2013 ; Tran et al, 2014 ; Cetrullo et al, 2015 ; Pavlatou et al, 2016 ; Uno and Nishida, 2016 ; Yuan et al, 2016 ; Donlon et al, 2017 ; Bartke and Quainoo, 2018 ; Morris et al, 2019 ; Singh et al, 2019 ; Blasiak et al, 2020 ; Zhang et al, 2020 ; Tabibzadeh, 2021 ). Majority of these genes are involved in cell/tissue responses to stress and damage that can contribute to the body’s ability to recover (resilience) and through this to its ability to survive to the oldest old age ( Ukraintseva et al, 2021 ). For the epistasis analysis, we selected 863 SNPs located in these genes based on the list of the SNPs genotyped on the IBC chip and available in both ARIC and CHS CARe data after QC ( Table 1A and Supplementary Table 2 ).…”

“…Many genes and their products have individually been found to significantly influence aging and survival traits in experimental models, including yeast, nematodes, flies, and mice. Genes for growth hormone and IGF1 receptors, FOXO transcription factors, target of rapamycin, p16, klotho, sirtuins, and some others, were repeatedly featured in experimental studies of aging and lifespan extension [e.g., Johnson et al, 2002 , 2013 ; Braeckman and Vanfleteren, 2007 ; Kenyon, 2010 ; Pavlatou et al, 2016 ; Uno and Nishida, 2016 ; Bartke and Quainoo, 2018 ; Singh et al, 2019 ; Tian et al, 2019 ; also reviewed in Ukraintseva et al (2021) ]. However, the majority of such genes have not been consistently replicated in humans, with few exceptions such as, e.g., FOXO3 and KL ( Arking et al, 2005 ; Willcox et al, 2008 ; Zeng et al, 2010 ; Nygaard et al, 2013 , 2014 ; Soerensen et al, 2016 ; Donlon et al, 2017 ; Revelas et al, 2018 ; Morris et al, 2019 ).…”

“…These pathways closely biologically interact and work in concert to decide on outcomes of cell responses to stress and damage, such as apoptosis, senescence, growth, division, autophagy, and repair, which may impact tissue resilience and, in turn, organismal survival and longevity ( Levine et al, 2006 ; Feng et al, 2007 ; Tran et al, 2014 ; Bitto et al, 2015 ; Werner et al, 2016 ; Ukraintseva et al, 2021 ; Figure 2 ). We, therefore, propose that the interplay between genes in these pathways may influence human lifespan.…”

Low Psychological Resilience in Older Individuals: An Association with Increased Inflammation, Oxidative Stress and the Presence of Chronic Medical Conditions

“…According to the current knowledge, biological (physical) resilience is a key manifestation of aging that contributes to an increased risk of mortality with age and eventually limits the human lifespan [42]. Although biological robustness (ability to resist deviations from the normal physiological state) generally declines with age, corresponding with the definite process of transition from a healthy to a frail state and with reduction in homeostatic reserves, it is assumed that biological resilience (ability to recover after deviation) can be increased, which provides the framework for anti-aging interventions [42]. At the phenomenological level, biological resilience is marked by the ability of an older individual to restore glucose levels or blood pressure or heart rate after deviations caused by a stressor, or by other abilities, such as wound healing or survival after an adverse health event.…”

Data_Sheet_1.docx

“…Many genes and their products have individually been found to significantly influence aging and survival traits in experimental models, including yeast, nematodes, flies, and mice. Genes for growth hormone and IGF1 receptors, FOXO transcription factors, target of rapamycin, p16, klotho, sirtuins, and some others, were repeatedly featured in experimental studies of aging and lifespan extension [e.g., Johnson et al, 2002Johnson et al, , 2013Braeckman and Vanfleteren, 2007;Kenyon, 2010;Pavlatou et al, 2016;Uno and Nishida, 2016;Bartke and Quainoo, 2018;Singh et al, 2019;Tian et al, 2019; also reviewed in Ukraintseva et al (2021)]. However, the majority of such genes have not been consistently replicated in humans, with few exceptions such as, e.g., FOXO3 and KL (Arking et al, 2005;Willcox et al, 2008;Zeng et al, 2010;Nygaard et al, 2013Nygaard et al, , 2014Soerensen et al, 2016;Donlon et al, 2017;Revelas et al, 2018;Morris et al, 2019).…”