Report: NIA workshop on translating genetic variants associated with longevity into drug targets

Abstract

To date, candidate gene and genome-wide association studies (GWAS) have led to the discovery of longevity-associated variants (LAVs) in genes such as FOXO3A and APOE. Unfortunately, translating variants into drug targets is challenging for any trait, and longevity is no exception. Interdisciplinary and integrative multi-omics approaches are needed to understand how LAVs affect longevity-related phenotypes at the molecular physiologic level in order to leverage their discovery to identify new drug targets. The NIA convened a workshop in August 2017 on emerging and novel in silico (i.e., bioinformatics and computational) approaches to the translation of LAVs into drug targets. The goal of the workshop was to identify ways of enabling, enhancing, and facilitating interactions among researchers from different disciplines whose research considers either the identification of LAVs or the mechanistic or causal pathway(s) and protective factors they influence for discovering drug targets. Discussions among the workshop participants resulted in the identification of critical needs for enabling the translation of LAVs into drug targets in several areas. These included (1) the initiation and better use of cohorts with multi-omics profiling on the participants; (2) the generation of longitudinal information on multiple individuals; (3) the collection of data from non-human species (both long and short-lived) for comparative biology studies; (4) the refinement of computational tools for integrative analyses; (5) the development of novel computational and statistical inference techniques for assessing the potential of a drug target; (6) the identification of available drugs that could modulate a target in a way that could potentially provide protection against age-related diseases and/or enhance longevity; and (7) the development or enhancement of databases and repositories of relevant information, such as the Longevity Genomics website (https://www.longevitygenomics.org), to enhance and help motivate future interdisciplinary studies. Integrative approaches that examine the influence of LAVs on molecular physiologic phenotypes that might be amenable to pharmacological modulation are necessary for translating LAVs into drugs to enhance health and life span.

Proteomics in aging research: A roadmap to clinical, translational research

“…Consistent with oxidative stress, in this study, significant correlations were also observed for other endogenous antioxidant enzyme family members, mitochondrial superoxide dismutase, SOD2, and CAT (Hayden & Tyagi, 2004), where they significantly decreased with age in plasma and liver. An overlap between proteins implicated in folate metabolism and proteins in immune related pathways was observed, consistent with recent studies (Ogg et al, 1997;Schork & Raghavachari, 2018).…”

“…In C.elegans, a null mutation of the FOXO ortholog DAF-16 is associated with life extension, likely through the modulation of carbohydrate metabolism and by enhancing stress response (Murtaza et al, 2017;Ogg et al, 1997). In humans, genetic variations of FOXO3A are associated with healthspan and longevity and are highly prevalent in centenarians (Schork & Raghavachari, 2018). Interestingly, in this literature review, we found several agerelated proteins regulated by FOXO transcription factors (Morris et al, 2015), including proteins implicated in energy homeostasis (agouti-related neuropeptide (AGRP)), ROS detoxification (catalase (CAT), superoxide dismutase 2 (SOD2)), and epidermal growth factor receptor (EGFR) signaling pathway (Table S2).…”

Protein signatures of centenarians and their offspring suggest centenarians age slower than other humans

“…However, an important lesson learned from studying centenarians and their offspring is that there are factors that protect some individuals from conditions associated with older ages (Andersen et al, 2012; Ismail et al, 2016; Partridge et al, 2018; Sebastiani et al, 2013). Given the finding that centenarians seem relatively protected from age‐related conditions, it is naturally of interest to study genetic and molecular profiles of both centenarians and their offspring to determine the genetic basis as to how and why some people age more healthily than others, in an effort to ultimately discover treatments for age‐related disorders (Kaeberlein et al, 2015; Schork et al, 2018; Sebastiani & Perls, 2012).…”

High-throughput sequencing analysis of nuclear-encoded mitochondrial genes reveals a genetic signature of human longevity

“…It is known that complex phenotypes are determined by multiple alleles functioning in combination (i.e., haplotypes), which should be extended to trans-genomic haplotypes and interactions between mtDNA-nDNA in future research [113][114][115]. With future developments in the integration of genomics, epigenomics, transcriptomics, proteomics, and metabolomics (-omics) data, there is greater hope that functional genetic variation in any pathway can be investigated for any phenotype, and in humans, on a more holistic system-biology level [1,2,116]. This kind of work will also help researchers plan for focused data-driven experiments aimed at explaining genotype-to-phenotype mechanisms.…”

“…Geroscience research has been focused on understanding the molecular mechanisms driving the cellular and physiological functional decline that comes with increased age [ 1 , 2 ]. Understanding the aging process to develop geroprotective interventions that extend health, quality of life, and independence during the final decades of life is one goal of geroscience research [ 2 , 3 ]. Geroscience research has succeeded in identifying key biological pathways, labeled as “hallmarks or pillars of aging,” that drive the aging process [ 4 , 5 ].…”