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Updated: Jan 6, 2026
A Suppressor Screen for the Characterization of Genetic Links Regulating Chronological Lifespan in Saccharomyces cerevisiae
Published on: September 17, 2020
Unveiling the genetic biomarkers for ageing: evidence from a large sample genome-wide association study and in vivo
Zhikang Cai1, Yue Yang2, Peng Qu3,4
1Department of Emergency Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Background:
Ageing, marked by cumulative molecular damage, now leaves most adults spending nearly a decade in poor health. To date, no therapies directly target the ageing process. We performed a large-scale genome-wide association study to identify potential drug targets for extending health span.
Methods:
By combining genetic and experimental evidence, we prioritise therapeutic targets with the potential to extend healthy lifespan. Using two-sample Mendelian randomisation (MR) across 26 152 expression quantitative trait loci instruments, we screened for causal links between 5430 potential drug target genes and four ageing phenotypes - frailty index (n = 175 226), HannumAge (n = 34 710), intrinsic epigenetic age acceleration (n = 34 710), and telomere length (n = 742 174). We re-evaluated high-confidence loci with summary-databased MR (SMR) and validated them by quantitative polymerase chain reaction (qPCR), Nissl staining, and Western blotting in three- and 20-month-old C57BL/6 mice. Finally, replication in a meta genome-wide association study (GWAS) of long-lived individuals vs. controls across 20 diverse cohorts upheld the association. This integrated genetic-experimental strategy prioritises candidate therapeutic targets for interventions aimed at extending healthy lifespan.
Results:
Two-sample MR mapped 47 gene-ageing links spanning frailty, telomere length, and two epigenetic clocks. The SMR confirmed 11 with consistent directions and heterogeneity in the dependent instrument support. Both qPCR and Western blot in three- and 20-month C57BL/6 mice confirmed age-dependent down-regulation of UBA7, PLA2G4B, and ATP8B4, validating their functional relevance. Finally, replication in a longevity meta-GWAS specifically confirmed the association for UBA7.
Conclusions:
These findings highlight UBA7, PLA2G4B, and ATP8B4 as promising targets for interventions aimed at extending health span, shedding light on the biological mechanisms of longevity.
Insights
Researchers identified UBA7, PLA2G4B, and ATP8B4 as key targets for extending health span. This study combines genetic and experimental data to find new therapies for aging.
Area of Science:
- Genetics
- Gerontology
- Pharmacology
Background:
- Aging is characterized by accumulating molecular damage, leading to reduced health span in adults.
- Current therapies do not directly address the aging process itself.
- There is a need for interventions that target the fundamental mechanisms of aging to extend healthy lifespan.
Purpose of the Study:
- To identify potential drug targets for extending health span by analyzing genetic associations with aging phenotypes.
- To prioritize therapeutic targets by integrating genetic and experimental evidence.
- To discover novel molecular pathways involved in longevity and healthy aging.
Main Methods:
- Conducted a large-scale genome-wide association study (GWAS) using Mendelian randomization (MR) across 26,152 expression quantitative trait loci (eQTL) instruments.
- Screened 5,430 potential drug target genes for causal links with four aging phenotypes: frailty index, HannumAge, intrinsic epigenetic age acceleration, and telomere length.
- Validated prioritized targets using summary-based MR (SMR), quantitative PCR (qPCR), and Western blotting in mouse models, followed by replication in a longevity meta-GWAS.
Main Results:
- Identified 47 gene-aging associations through two-sample MR, involving frailty, telomere length, and epigenetic clocks.
- Confirmed 11 associations using SMR, with consistent directions of effect.
- Validated age-dependent downregulation of UBA7, PLA2G4B, and ATP8B4 in mice, with UBA7 specifically replicated in a longevity meta-GWAS.
Conclusions:
- UBA7, PLA2G4B, and ATP8B4 are promising therapeutic targets for interventions aimed at extending health span.
- These findings provide insights into the biological mechanisms underlying longevity.
- The integrated genetic and experimental approach effectively prioritizes targets for anti-aging therapies.
