Young Plasma from Pigs Reduces Epigenetic Age in Old Rats
One interesting question in the development of new epigenetic clocks to measure biological age, particularly now that a large consortium of researchers has published a universal mammalian clock, is how one demonstrates that a new clock is in some way useful enough or interesting enough to spend time on. There are, after all, many published clocks at this point, and we might expect that the research community will attempt to standardize on the new universal clock. Why use another novel clock? One answer might be that the clock is optimized to give a large signal under a particular set of circumstances. Hence we arrive at studies like the one noted here, in which researchers demonstrate that their novel clock performs in a potentially useful way when assessing the results of plasma transfer from young individuals to old individuals between mammalian species.
Young blood plasma is known to confer beneficial effects on various organs in mice and rats. However, it was not known whether plasma from young pigs rejuvenates old rat tissues at the epigenetic level; whether it alters the epigenetic clock, which is a highly accurate molecular biomarker of aging. To address this question, we developed and validated six different epigenetic clocks for rat tissues that are based on DNA methylation values derived from n=613 tissue samples. As indicated by their respective names, the rat pan-tissue clock can be applied to DNA methylation profiles from all rat tissues, while the rat brain-, liver-, and blood clocks apply to the corresponding tissue types. We also developed two epigenetic clocks that apply to both human and rat tissues by adding n=1366 human tissue samples to the training data.
We employed these six rat clocks to investigate the rejuvenation effects of a porcine plasma fraction treatment in different rat tissues. The treatment more than halved the epigenetic ages of blood, heart, and liver tissue. A less pronounced, but statistically significant, rejuvenation effect could be observed in the hypothalamus. The treatment was accompanied by progressive improvement in the function of these organs as ascertained through numerous biochemical/physiological biomarkers and behavioral responses to assess cognitive functions. An immunoglobulin G (IgG) N-glycosylation pattern shift from pro-to anti-inflammatory also indicated reversal of glycan aging. Overall, this study demonstrates that a young porcine plasma-derived treatment markedly reverses aging in rats according to epigenetic clocks, IgG glycans, and other biomarkers of aging.