Reversal of biological age in multiple rat organs by young porcine plasma fraction

Abstract

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 adult 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, behavioral responses encompassing 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.

Young Plasma Rejuvenates Blood DNA Methylation Profile, Extends Mean Lifespan, and Improves Physical Appearance in Old Rats

“…Therefore, the treated rats would be undergoing a significant, albeit modest, epigenetic rejuvenation. This is in line with a previous study reporting that treatment of old rats with a porcine plasma fraction markedly sets back their epigenetic age ( 9 ).…”

“…Thus, it has been reported that treatment with human cord plasma increases synaptic plasticity and hippocampal-dependent cognition in aged mice and that one of the effectors of these improvements may be a circulating factor known as tissue inhibitor of metalloproteinases 2 ( 45 ). In old rats, there is evidence that administration of plasma proteins may exert a marked reversal of epigenetic age ( 9 ). In the present study we show, for the first time to our knowledge, that lifelong treatment of old rats with young rat plasma induces a moderate but significant epigenetic rejuvenation, extends their mean lifespan and improves the physical appearance of the animals (which, for instance, show a whither and smoother fur), an effect that might be at least in part mediated by the IGF-1/IIS system as well as homeostatic cytokine and chemokine networks.…”

“…In mice, it has been reported that repeated injections of young plasma do not significantly affect either median or maximal lifespan ( 8 ). In contrast, a more recent study in old rats reported that a porcine plasma fraction (termed elixir or E5) markedly reversed the epigenetic age of the animals, which also showed functional and metabolic signs of rejuvenation ( 9 ). The latter report prompted us to assess the effects of young rat plasma on the lifespan, epigenetic age, and healthspan of old female rats.…”

AI Health Agents: Pathway2vec, ReflectE, Category Theory, and Longevity

“…Blood tests are used measure these factors, for example, the plasma protein signature for eleven organ-specific aging clocks (brain, muscle, artery, heart, lung, immune, liver, kidney, pancreas, adipose, intestine) to find 20% of 5,676 healthy adults already having accelerated aging in at least one organ (Oh et al 2023). Epigenetic clocks confirmed the rejuvenation of six tissues getting younger as measured by DNA methylation values (in an animal parabiosis model) (Horvath et al 2024).…”

Organ specificity and commonality of epigenetic aging in low- and high-running capacity rats

“…Epigenetic clocks are a promising aging biomarker that can estimate biological age across organs based on age-related changes in DNA methylation patterns, and have demonstrated high predictive power for age-related disease onset and mortality in humans 19,20 . Epigenetic clocks have also been developed in rodents such as mice 21–24 and rats 17,25 and pan-species clocks have been proposed, including human-rat pan-tissue clock 26,27 . These findings and latest studies 28 suggest that age-related changes in DNA methylation patterns are a common mechanism of aging across mammals and, simultaneously, provide a useful tool for evaluating the effectiveness of intervention strategies to delay aging in a relatively short timescale.…”