Can We Turn Back The Clock? Parabiosis Research Suggests Yes

(Posted on Wednesday, September 6, 2023)

What if you could turn back the clock on biological age? What if, instead of growing older by the day, you grew younger by the day? New research by scientists at Harvard Medical School suggests this may be less science fiction than it seems. Published in Nature Aging, Bohan Zhang and colleagues discovered that old mice that have been connected to young mice for an extended period begin to “reverse age” and live up to 9% longer than their peers. Although still in its early stages, their work yields exciting implications for the future of aging and longevity.

Two Peas in a Pod: Parabiosis 

To connect the old mice to the young mice, the researchers used a laboratory technique called parabiosis. Think of this as a very involved kind of blood transfusion. Whereas during a normal transfusion, blood is taken from one mouse and separately infused into another, during parabiosis the two animals are surgically joined; an ongoing, real-time transfusion. So instead of simply exchanging blood, animals connected via parabiosis develop a single, shared physiological system. In a sense, they merge together, exchanging everything from blood to hormones.

Zhang et al. connected young mice to young mice, old mice to old mice, and young mice to old mice. The first two acted as control groups, providing the scientists with a reference point against which to compare the results of the young-to-old parabiosis. Throughout parabiosis, the mice had their liver and their blood analyzed for various age-related biomarkers.

The mice were left joined together for three whole months, after which they were surgically separated —“detached.” They were then given one month to recover before having their physiological data recorded. A few of the mice were allowed to live freely until their natural death to help the researchers understand the effects of parabiosis on longevity.

A schematic diagram of the study design. ‘ISO’ refers to isochronic parabiosis: the surgical joining of two animals of the same age (young-to-young or old-to-old). ‘HET’ refers to heterochronic parabiosis: the surgical joining of two animals of different ages (young-to-old). SOURCE: Zhang et al. 2023 https://doi.org/10.1038/s43587-023-00451-9

Biological Age vs Chronological Age

We all age. Every rotation around the sun adds one additional year to our lives, there’s no way around that. But, it’s becoming increasingly clear that we don’t all age at the same speed: although two people may share the same “chronological” age, they can be very different “biological” ages. The former simply refers to the amount of birthdays they’ve celebrated, but the latter refers to markers of aging at the level of blood, organs, and genetics. Your biological age is your “true”, physical age. Your risk of developing age-related diseases, like heart disease or cancer, is based on your biological age — in some cases this may be lower than chronological age, in others, it may be higher.

How do you measure biological age? There are a number of ways to do this, but one of the most accurate is through the use of “epigenetic clocks”. Discovered in 2011 by Steve Horvath, such epigenetic clocks are based on a process known as DNA methylation. Even though our genetic code itself —our DNA— does not change over the course of our lifetime, the way in which it is expressed does. This is called epigenetics. DNA methylation is a key mechanism of epigenetics; molecules called methyl groups are added along the length of DNA, turning certain genes “off” or “on”. Horvath’s prescient contribution was the recognition that the way DNA is methylated follows a pattern, one that can be traced over time and correlates with chronological age. Knowing the pattern allows us to read DNA methylation like a clock.

Long, Youthful Lives

Bohan Zhang and his fellow researchers made use of epigenetic clocks to study the effects of parabiosis on the mice. They noticed that the old mice that had been joined to young mice displayed signs not only of slowed aging, but even reverse aging: their DNA methylation signatures were consistently “younger” than their chronological age. Indeed, the methylation clocks suggested a decrease in biological age by up to 30%. This was not true of the old mice that had been surgically joined to other old mice. Nor was it true of old mice that had been non-surgically joined to younger mice, ruling out the possibility that the reversal of epigenetic age was due to increased movement or exercise from being connected to a young mouse.

Crucially, the changes to biological age persisted even after detachment from the younger mice. And they weren’t restricted to the blood alone, but to muscle tissue, the liver, and the nervous system too. Reversal of biological age also correlated to longer life spans, with the older mice that had been joined to younger mice living six to nine percent longer than those that had been joined to other older mice. Similarly, changes to gene expression mirrored what has been observed in longevity interventions and opposed changes usually seen during aging.

Takeaways

In this exciting study, Zhang et al. have shown that old mice can have their lifespan extended and their aging slowed by being joined to younger mice. The benefits of this procedure persist even after detachment. Indeed, along with increased lifespan, the old mice also displayed signs of improved organ health. Although chronological aging is inevitable, biological aging is starting to look a lot more reversible.