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J Gerontol A Biol Sci Med Sci. 2019 Nov 13;74(Supplement_1):S61-S71. doi: 10.1093/gerona/glz206.

Genetic Support for Longevity-Enhancing Drug Targets: Issues, Preliminary Data, and Future Directions.

Author information

1
Graduate Program in Bioinformatics and Systems Biology, University of California-San Diego, Phoenix, Arizona.
2
Institute for Integrative Genome Biology, University of California, Riverside, Phoenix, Arizona.
3
Department of Quantitative Medicine and Systems Biology, The Translational Genomics Research Institute (TGen), Phoenix, Arizona.
4
Department of Medical Oncology, City of Hope National Medical Center, Duarte, California.
5
Department of Pathology, Ann Arbor.
6
Glenn Center for the Biology of Aging, University of Michigan, Ann Arbor.
7
Department of Population Sciences, City of Hope National Medical Center, Duarte, California.
8
Department of Psychiatry, University of California-San Diego.
9
Department of Family Medicine and Public Health, University of California-San Diego.

Abstract

Interventions meant to promote longevity and healthy aging have often been designed or observed to modulate very specific gene or protein targets. If there are naturally occurring genetic variants in such a target that affect longevity as well as the molecular function of that target (eg, the variants influence the expression of the target, acting as "expression quantitative trait loci" or "eQTLs"), this could support a causal relationship between the pharmacologic modulation of the target and longevity and thereby validate the target at some level. We considered the gene targets of many pharmacologic interventions hypothesized to enhance human longevity and explored how many variants there are in those targets that affect gene function (eg, as expression quantitative trait loci). We also determined whether variants in genes associated with longevity-related phenotypes affect gene function or are in linkage disequilibrium with variants that do, and whether pharmacologic studies point to compounds exhibiting activity against those genes. Our results are somewhat ambiguous, suggesting that integrating genetic association study results with functional genomic and pharmacologic studies is necessary to shed light on genetically mediated targets for longevity-enhancing drugs. Such integration will require more sophisticated data sets, phenotypic definitions, and bioinformatics approaches to be useful.

KEYWORDS:

Human Aging; Longevity; Mortality

PMID:
31724058
DOI:
10.1093/gerona/glz206

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