MANF Declines with Age and is Required for Parabiosis Benefits to the Liver

Researchers have identified MANF as a factor responsible for at least some of the benefits provided to the older of two animals with linked circulatory systems. Joining two animals, usually mice, in this way is known as parabiosis. It has been used a tool to explore the role of the signaling environment of blood and tissues in aging. Stem cell function, for example, declines with age, and a sizable part of that decline appears to be a reaction to the changing, damaged environment rather than inherent damage in the stem cells themselves. Thus signals must exist to mediate the altered behavior of cells in response to what is going on around them.

If signals exist, then they can be overridden. Some research groups are searching for factors in young blood that might be used to boost stem cell function and tissue function in old mice. Other groups are convinced that the effect is due to dilution of harmful factors in old blood rather than the addition of helpful factors in young blood. The evidence on both sides is compelling, and the conflicts are yet to be resolved. While that debate is ongoing, it seems reasonable to expect further discoveries of signals and regulators that can increase stem cell activity in old tissues to some degree. That tends to help spur greater tissue maintenance and repair, but with some presently unknown additional cancer risk as damaged cells are forced back to work.

Older mice who are surgically joined with young mice in order to share a common bloodstream get stronger and healthier, making parabiosis one of the hottest topics in age research. Researchers report that MANF (mesencephalic astrocyte-derived neurotrophic factor) is one of the factors responsible for rejuvenating the transfused older mice. Researchers also show the naturally-occurring, evolutionarily-conserved repair mechanism protects against liver damage in aging mice and extends lifespan in flies.

While researchers have yet to understand why MANF levels decrease with age, MANF deficiency has obvious hallmarks. Flies genetically engineered to express less MANF suffered from increased inflammation and shorter lifespans. MANF-deficient mice had increased inflammation in many tissues as well as progressive liver damage and fatty liver disease. Older mice who shared blood with MANF-deficient younger mice did not benefit from the transfusion of young blood.

"MANF appears to regulate inflammatory pathways that are common to many age-related diseases. We are hoping its effects extend beyond the liver, we plan to explore this in other tissues. The search for systemic treatments that would broadly delay or prevent age-related diseases remains the holy grail of research in aging. Given that MANF appears to modulate the immune system, we are excited to explore the larger implications of its therapeutic use. We are also cautious. There are many tissues and organ systems to evaluate in terms of MANF and we have yet to determine its effects on lifespan in the mouse."