Matt recently exchanged a lively correspondence about biological age with Harold Katcher, cofounder of a stealth biotechnology company and inventor of E5. E5 is a compound consisting of the purified exosome fraction of blood from young piglets—in other words, young pig blood. Katcher recently co-published a paper suggesting that injecting this young pig blood into rats made rats younger on several biological aging measures, including inflammatory markers and epigenetic aging signatures. Indeed, Katcher has injected E5 into his own right hand and presented differences in the appearance of his right and left hands on social media.

Putting pig blood into other animals (and into ourselves!) to reverse biological age might seem like a crazy thing to do. But this idea actually stems from a methodology with a decades-long history called heterochronic parabiosis, an area of research that explores the effects of joining the circulatory systems of different-aged organisms. In this experimental technique, researchers surgically connect two animals, typically mice, of disparate ages so that they share a common bloodstream. This union leads the older and younger individuals to exchange not just blood cells but also signaling molecules, growth factors, and other circulating factors. Remarkably, when an older animal is paired with a younger counterpart, it often experiences improvements in various aspects of health and tissue function, while the younger partner may exhibit corresponding signs of accelerated aging. The mechanisms underlying these effects are complex, multifaceted, and very much still under investigation.

In this episode, Matt takes a magnifying glass to E5: what we know about the compound, how it affects lifespan, and how its impact on lifespan stacks up with that of other longevity inventions such as caloric restriction and rapamycin. He discusses whether Harold's recent paper truly proves a reversal of biological age and where his findings fit into the larger body of literature in the field. He also gives us a window into the methodology of heterochronic parabiosis, what the primary data about life expectancy gains through this intervention show, and whether heterochronic parabiosis-inspired interventions such as E5 are realistic approaches to human lifespan extension.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

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

This paper details the experiment featured in this podcast episode as well as the creation of epigenetic clocks for rat tissues. Scientists examined the effect of a plasma fraction from young adult pigs on these epigenetic clocks, and found that the treatment reduced epigenetic age, as measured by the clocks, by up to 30 percent across several rat organs. E5 also improved other parameters such as inflammatory markers and grip strength. The paper did not present lifespan data for the treated rats.

The Retardation of Aging in Mice by Dietary Restriction: Longevity, Cancer, Immunity and Lifetime Energy Intake

This decades-old paper presents results showing a significant lifespan extension in mice undergoing caloric restriction, an intervention that Matt describes as "arguably the gold standard" for rodent lifespan extension. The longest-lived mice in this paper averaged 53 months of life (average mouse lifespan is 12 to 18 months). It would have been interesting to do an apples-to-apples comparison of E5's effects on mouse lifespan to that of the caloric restriction this paper describes.

Studies that shed new light on aging

In this 2013 paper, Katcher describes his disagreement with the "wear and tear" or "accumulated damage" model of aging, which suggests that the primary driver of aging is a gradual accumulation of damage to cells and tissues over time that eventually leads to declines in their function and the onset of age-related diseases. He proposes paying greater attention to rejuvenation of aged cells, possibly via heterochronic plasma exchange, on the thesis that it is actually factors in the blood that regulate aging, and that young plasma carries factors that enable cellular youthfulness.

Harold Katcher's rejuvenated hand self-experiment

Katcher applied a topical version of E5 to his own right hand in 2022. This post from The Longevity Newsletter presents a side-by-side photographic comparison of his right (E5) and left (no E5) hands. According to Katcher, E5 thickened the skin and improved the color of as well as erased scars and wrinkles from his right hand.

Heterochronic parabiosis: historical perspective and methodological considerations for studies of aging and longevity

This review covers the history of heterochronic parabiosis, from the earliest documented instances of experimentation with animal grafting to 21st-century studies of regeneration. It also presents the methodology, technical challenges, and limitations of heterochronic parabiosis, such as mortality risk and parabiotic disease.