Parabiosis experiments, in which the circulatory systems of young and old mice are joined together, revealed that young blood rejuvenates the tissues of elderly mice. Since this discovery, the search for factors in young plasma (the liquid part of the blood that carries the cells) with the power to reverse ageing has been ongoing. Finding such factors is challenging, as plasma contains thousands of different molecules, some of them in very small concentrations. Nevertheless, research has revealed factors present in the plasma that change during ageing and appear to be involved in rejuvenation, at least in animal models.
Apelin is a hormone that regulates processes throughout the body, including in the heart, brain, digestive system and muscles. Apelin levels in the blood decline into old age, and this seems to play a role in the ageing process as the organs of mice modified to lack apelin age faster.
In both ageing mice and humans, one of the ways that exercise helps prevent the decline in muscle mass is by stimulating the production of apelin. Administration of apelin in older mice increases their muscle function by promoting synthesis of proteins and mitochondria, and has also been shown to help regenerate muscle stem cells.
β2M is a protein that helps the immune system to recognise pathogens that hide inside cells. While a deficiency of β2M weakens the immune system, elevated β2M appears to be associated with ageing, frailty and mortality. In particular, β2M appears to influence cognitive function, as β2M-deficient mice display superior cognitive performance. Administration of β2M, on the other hand, impairs the growth of new brain cells and reduces cognitive function.
Cadherin-13 is a protein that can regulate the growth and migration of cells. It plays an important role in bone tissue, where it inhibits the production of osteoclasts – cells that break down bone tissue.
While found primarily on the surface of cells, cadherin-13 is also found in the blood, where its levels decline during ageing. In mice, this seems to be linked to age-associated bone loss, and bone loss can be slowed by administration of cadherin-13.
NAD (nicotinamide adenine dinucleotide) is an essential molecule for the production of the cell’s primary energy source, ATP, as well as fulfilling many other functions. Levels of NAD decline with age, and this is thought to contribute to multiple drivers of ageing including DNA damage and inflammation.
eNAMPT found in the blood is a key enzyme in the synthesis of NAD, but it declines with age. Not only do levels of circulating eNAMPT correlate closely with age in both mice and humans, but boosting eNAMPT in mice maintains NAD levels during ageing and extends their lifespan.
Oxytocin is a hormone that might be best known for its role in social bonding. However, oxytocin plays a role in a variety of different tissues, including bone, where it stimulates the production of osteoblasts (cells that build new bone). Circulating oxytocin appears to decline with age, particularly in women following the menopause, and this is associated with loss of bone density. Consistent with this observation, supplementation with oxytocin reverses bone loss in oxytocin-deficient rodents.
The decline of oxytocin also seems to contribute to the defects in muscle regeneration. Oxytocin-deficient mice show accelerated muscle decline, and oxytocin has also been found to rejuvenate muscle stem cells.
Circulating plasma factors involved in rejuvenation: https://doi.org/10.18632/aging.103933
Downregulation of the Apelinergic Axis Accelerates Aging, whereas Its Systemic Restoration Improves the Mammalian Healthspan: https://doi.org/10.1016/j.celrep.2017.10.057
The exerkine apelin reverses age-associated sarcopenia: https://doi.org/10.1038/s41591-018-0131-6
β2-microglobulin is a systemic pro-aging factor that impairs cognitive function and neurogenesis: https://doi.org/10.1038/nm.3898
Plasma proteomic profiling of young and old mice reveals cadherin-13 prevents age-related bone loss: https://doi.org/10.18632/aging.103184
Extracellular Vesicle-Contained eNAMPT Delays Aging and Extends Lifespan in Mice: https://doi.org/10.1016/j.cmet.2019.05.015
Oxytocin Controls Differentiation of Human Mesenchymal Stem Cells and Reverses Osteoporosis: https://doi.org/10.1634/stemcells.2008-0127
Oxytocin is an age-specific circulating hormone that is necessary for muscle maintenance and regeneration: https://doi.org/10.1038/ncomms5082