Small, non-coding RNAs that regulate gene expression but are not translated into proteins could affect the lifespan of older people, research suggests.
The epigenetic factors, which modulate gene expression without altering the underlying DNA sequence, could one day act as promising biomarkers and therapeutic targets that extend longevity.
Blood levels of nine piwi-interacting (pi)RNAs—the largest class of small, non-coding RNAs in animal cells—were all reduced among individuals who lived longer in the study, according to the findings in Aging Cell.
Other small, non-coding RNAs called micro (mi)RNAs,—which are just 22 nucleotides in length on average—were also identified as having a role in survival.
The small, non-coding RNAs were only able to meaningfully predict short- and medium-term survival, offering less value when forecasting extended to a decade.
Nonetheless, lead researcher Virginia Byers Kraus, PhD, from Duke Molecular Physiology Institute, maintained: “These results suggest that simple blood tests measuring piRNAs might one day help doctors better understand health and aging—and possibly even guide new treatments to help people live longer, healthier lives.”
Small non-coding RNAs have emerged as important regulators of various biological processes relating to aging.
PiRNAs help protect DNA in reproductive cells, maintaining genomic stability by silencing jumping genes through cytosine methylation.
miRNAs, first discovered in the nematode worm Caenorhabditis elegans in 1993, primarily function as post-transcriptional regulators of gene expression, binding to complementary messenger RNA sequences to inhibit the translation of proteins.
Byers Kraus and team examined the predictive value of 828 small, non-coding RNAs in 121 community-dwelling older adults, aged at least 71 years of age. These consisted of 687 miRNAs and 141 piRNAs.
Lower circulating levels of piRNAs were consistently associated with 2- and 5-year survival. A distinct set of miRNAs also played a role in survival—for example miR-153-3p was positively associated with 5-year survival, aligning with its known role in cellular stress response pathways.
“These results reflect the importance of miRNAs in proteostasis and cellular response to aging, particularly in hematopoietic stem cell function,” the researchers reported.
Only four small-noncoding RNAs, all piRNAs, were estimated as direct causal determinants of 2-year survival and were shared predictors of 5-year survival. There was no overlap of 2-year or 5-year survival predictors with 10-year small, non-coding RNA predictors.
A predictive model performed strongly when incorporating small, non-coding RNAs, age, and clinical variables that included demographics, lifestyle, mood, physical function, standard clinical laboratory tests, lipids and metabolites, and medical conditions.
It produced a cross-validated area under the receiver operating characteristic curve (AUC) of 0.92 for 2-year survival under discovery conditions, which was 0.87 under external validation.
Nine piRNAs, all reduced in longer-lived individuals, were identified as potential therapeutic targets.
Researchers found that using six piRNAs alone, or five combined with two clinical measures, could predict 2-year survival with AUCs of 0.83 and 0.85, respectively.
“The proposed 5-piRNA plus 2-clinical-variable model is well suited for clinical translation,” the authors noted.
They added: “Our findings provide compelling evidence that circulating [small, non-coding] RNAs—especially piRNAs—are powerful predictors of survival in older adults and potential biomarkers of longevity.
“The development of a streamlined, high-accuracy predictive model, along with the identification of specific piRNAs associated with survival, underscores the biological relevance of these molecules in aging.
“Notably, our results suggest that piRNAs may influence longevity through novel mechanisms beyond their traditional roles in the germline, offering exciting opportunities for therapeutic strategies to promote healthy aging.”
