Fight Aging!

The normally secretive California Life Company, or Calico, recently shared some of their investigations into the rejuvenation that takes place in the earliest stages of the reproductive process - parents are old and children are young, so a form of rejuvenation must happen at some point, or reproductive cells must be exceptionally well protected from aging. The Calico team showed that in nematodes and frogs, egg cells, or oocytes, undergo a burst of cellular housekeeping when they are used, clearing out damaged proteins. It is thought that something similar happens in mammalian early embryonic development, a process that also seems to be triggered in part by induced pluripotency. Is this all useful and relevant to efforts to produce rejuvenation therapies? Here is a lengthy commentary from the SENS Research Foundation, whose founder has been one of a number of researchers very critical of Calico Labs in the past:

Some readers got the impression that this study had uncovered a special molecular mechanism that allows these nematodes' oocytes uniquely to stay "young," even as the body as a whole grew old. This impression may have been reinforced by a quote from one researcher, contrasting the aging of the human body with the (seeming) "immortality" of the germline (the "line" of sperm and egg genes that actually passes from generation to generation): "You take humans - they age two, three or four decades, and then they have a baby that's brand new."

Taken together, some readers came away with the suggestion that the fact that babies are born young implies the ability of oocytes to "sweep themselves clean" of their adult parents' lifetime burden of deformed proteins, and excitedly hoped that the tricks that oocytes use to execute this feat could somehow be engineered into aging cells elsewhere in the body to keep our muscle and brain cells young. Unfortunately, no such tricks emerged from this study, nor are they likely to. This study adds substantial insight to a body of work on nematode (and later frog) oocyte biology sparked by a discovery made by French scientists in 2010 and prior work in yeast and in mouse embryos. However, there is nothing here that can be exploited for developing anti-aging therapies.

The real finding of the paper is better captured by its own title than the newspaper headlines: "A lysosomal switch triggers proteostasis renewal in the immortal C. elegans germ lineage." The key word in there is not "immortal," but "renewal" - renewal of "proteostasis," the somewhat equivocal concept of the young cell's dynamic maintenance of stably low levels of damaged proteins. As it turns out, the "renewal" in question is a reactivation of the normal "proteostatic" activity of the lysosome - the cell's recycling center, where old and damaged proteins are broken down into raw materials that can then be reused to build new proteins.

While oocytes are held in storage, they adopt a metabolically dormant state to conserve energy and reduce the production of metabolic wastes. This much is just as true in mammals as it is in the roundworms and frogs studied in this new report. What the new study uncovered is a particular energy-conservation strategy these animals' oocytes use. No special rejuvenative power is involved in this process: other cells clean up these same wastes routinely, as a matter of day-to-day housekeeping, instead of letting them build up until it's absolutely necessary to get rid of them.

Despite the lengths to which the body goes to maintain only viable, "young" eggs, oocytes do still manage to degenerate with age, which is part of the reason why older parents are less fertile. The silver lining in all of this bad news: because the nature of the degenerative aging process in the reproductive system is not different from the aging of the rest of the body at the cellular and molecular level, the "damage-repair" heuristic of rejuvenation biotechnology can be applied to rejuvenate the aging reproductive system just as it can to the rejuvenation of the rest of our bodies.

We're not going to solve the degenerative aging process by borrowing any special tricks from the oocyte. The oocyte doesn't really have any tricks for us to profitably exploit - and more importantly, no cell in the body is naturally able to remove or repair many of the kinds of damage that accumulate in aging bodies and ultimately lead to age-related disease, debility, and death. The oocyte has no way to clear beta-amyloid from aging brains, or TTR amyloid from aging hearts - nor to cleave AGE crosslinks from aging arteries, as they are subject to none of this damage. It has no internal means to replace cells that are lost to aging damage, and is no more able to degrade the truly stubborn intracellular aggregates that accumulate in aging cells than any other cell type. For that, we need a new class of medicines that can do what we can't do on our own: remove, repair, replace, or render harmless the cellular and molecular damage of aging in our tissues. It is when we develop rejuvenation biotechnologies and deploy them comprehensively that we will finally be able to effectively "turn back time" for aging bodies as a whole.

Link: http://www.sens.org/research/research-blog/question-month-16-any-rejuvenation-relevance-roundworm-reproduction