The Role of Blood Factors

A major hallmark of aging is that regenerative properties significantly decline in most tissues. In 2005, Dr. Thomas Rando’s laboratory at Stanford University used heterochronic parabiosis, the connection of the circulatory systems of a young and an old animal, to demonstrate that factors derived from a young animal are able to activate molecular signaling pathways of an old animal, leading to increased tissue regeneration1,2. These findings demonstrated for the first time that the age-associated impairment of cell function is induced to a significant extent by the molecular composition of the surrounding milieu rather than by cell specific changes alone.

Image by Tamily Weissman

Image by Tamily Weissman. The Brainbow mouse was produced by Livet J, Weissman TA, Kang H, Draft RW, Lu J, Bennis RA, Sanes JR, Lichtman JW. Nature (2007) 450:56-62

Dr. Tony Wyss-Coray and Dr. Saul Villeda, in collaboration with Dr. Rando, subsequently reported that the old systemic environment negatively affects adult neurogenesis in brains of young heterochronic parabiont animals, and conversely, a young environment can increase neurogenesis in the old brain3. This led to the discovery that soluble factors – rather than cells – in old blood are responsible for the decrease in synaptic plasticity and impair learning and memory. They discovered certain protein factors3,4 that impair adult neurogenesis and cognition in mice. Other groups demonstrated rejuvenating effects in a wide range of tissues and organs in old heterochronic parabionts.

In 2014, Villeda, Wyss-Coray and colleagues advanced further to show that such effects could be achieved without permanently connecting circulatory systems thus opening up the potential for a translatable therapeutic route. They reported that plasma from young mice, repeatedly injected into old mice, can increase memory function by targeting classical molecular pathways known to be involved in cognition and stimulate morphological processes in the hippocampus5. Multiple aging factors or rejuvenating factors exist within plasma that originate from and target different tissues.

These recent scientific data support the existence of beneficial “rejuvenating” factors in young plasma and the presence of “age-promoting” factors in old plasma. Both classes of agents offer therapeutic opportunities for the treatment of cognitive dysfunction and other age-related diseases.

  1. Conboy IM, Conboy MJ, Wagers AJ, et al. (2005) Rejuvenation of aged progenitor cells by exposure to a young systemic environment. Nature 433:760-764.
  2. Brack AS, Conboy MJ, Roy S, et al. (2007) Increased Wnt signaling during aging alters muscle stem cell fate and increases fibrosis. Science. 317:807-810.
  3. Villeda SA, Luo J, Mosher KI, et al. (2011) The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature 477:90-94.
  4. Smith LK, He Y, Park JS, et al. (2015) β2-microglobulin is a systemic pro-aging factor that impairs cognitive function and neurogenesis. Nature Medicine.
  5. Villeda SA, Plambeck KE, Middeldorp J, et al. (2014) Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice. Nature Medicine 20:659-663.