A great many studies have used large human population data sets to show statistical relationships between specific gene variants or specific protein levels on the one hand and age-related disease and mortality on the other. Near all of these relationships represent a small effect size, and further fail to replicate in different study populations. Still, researchers keep trying. Some successful replications have been achieved, and a few genes and proteins are generally accepted as being longevity-associated in humans. It remains unclear as to whether they are of any great practical relevance to extending the healthy human life span, however. Some, such as klotho and APOE, are the subject of programs to develop treatments to improve late-life health or treat specific age-related diseases.
Today's open access paper is an interesting example of establishing a protein association with increased mortality and accelerated aging, and then tracing it back to a relationship with lifestyle factors, cancer incidence, and mechanisms relating to cellular senescence. Senescent cells accumulate with age and are an important contributing factor in age-related disease and loss of function. The research focuses on PDAP1, a protein that appears to be upregulated in stressed and senescent cells, and also acts to induce senescence in bystander cells. One would imagine that the next step here is to run studies of PDAP1 inhibition in aged mice, to see whether long term health and mortality are improved.
Identifying factors affecting lifespan, including genes or proteins, enables effective interventions. We prioritized potential drug targets and provided insights into biological pathways for healthy longevity by integrating Mendelian randomization, cohort, and experimental studies. We identified causal effects of tissue-specific genetic transcripts and serum protein levels on three longevity outcomes: the parental lifespan, the top 1% and 10% extreme longevity, utilizing Mendelian randomization and multi-traits colocalization, combining the latest genetics data of gene expression (eQTLGen and GTEx) and proteomics (4746 proteins from five studies). We then evaluated associations of these potential genetic targets with mortality risk and life expectancy in the UK Biobank cohort. We performed in vitro cellular senescence experiments to confirm their effects.
Fourteen plasma proteins and nine transcripts in whole blood had independent causal effects on longevity, where a cascading effect of both the tissue-specific transcripts and plasma proteins of LPA, PDAP1, DNAJA4, and TMEM106B showed negative effects on longevity. PDAP1, also known as platelet-derived growth factor subunit A-associated protein 1, is a multi-tissue-expressed protein in the pathway that suppresses T-cell function. It has become a potential target for c-myc and contributes to carcinogenesis. Mediation analysis suggested that PDAP1 decreased longevity via decreased SHBG, increased waist circumference, blood pressure, smoking, and alcohol consumption in addition to cancer.
Studies also suggested that lower SHBG levels may increase testosterone levels, leading to cardiovascular risk factors. The harmful effects of altered diseases or traits were also consistent with the epigenetic acceleration of aging caused by PDAP1. These results were consistent with our findings from the UK Biobank, where the plasma level of PDAP1 was significantly associated with all-cause mortality and life expectancy. In addition, the in vitro experiments indicated targeting PDAP1 offers a dual advantage by potentially promoting senescence in cancerous cells to inhibit growth, while delaying senescence in healthy cells to enhance tissue regeneration and extend cellular lifespan.
View the full article at FightAging
