Parents and their germline cells are biologically old, and yet developing offspring produced from the germline are biologically young. Therefore a form of cellular rejuvenation takes place somewhere between the start and the end of reproduction in multicellular organisms, whether they are nematode worms of a few hundred cells, or vastly larger and more complex species such as our own. New research on this topic from the usually secretive research groups at Calico was widely announced today; it is focused on the nematode Caenorhabditis elegans, but the findings are probably of relevance to the processes of rejuvenation that take place in mammalian reproduction. Aging is a matter of accumulated damage, of quite similar forms in nematodes and mammals: to make offspring young, all of this damage must be cleared away, or the germline shielded from it.
The rejuvenation that occurs in mammalian zygotes is not all that well characterized, though you'll find papers on the topic from recent years. It appears to overlap with processes observed to take place when cells are reprogrammed into a state of induced pluripotency: researchers have seen mitochondrial damage repaired, for example. This present work in nematodes is interesting for its focus on the lysosome and clearance of metabolic waste, as there isn't all that much work on what happens to such waste during induced pluripotency or in early mammalian embryonic development. Clearly it has to be successfully removed if present in order for offspring to be young, but this doesn't necessarily mean that the various mammalian processes of rejuvenation are anything like those of nematodes in their details and ordering, even if there are strong similarities at the high level.
The research here is intriguing for extending the findings in nematodes to frogs - give it a few years and we'll no doubt be seeing the study results for mammals. In mammals, early life rejuvenation must accomplish the same goal as it does in frogs and nematodes, regardless of how it is organized, which is to ensure that offspring are biologically young. Further, it must take place when those offspring are still a collection of just a few cells, as these processes would be highly disruptive and probably fatal if they took place throughout a more developed, complex organism. But perhaps such processes of rejuvenation could be selectively targeted to small and vital collections of cells. Perhaps it already takes place in some such cell populations as a way to maintain their function for a lifetime; consider stem cells, for example. This remains to be seen, as does how useful the rejuvenation processes that make offspring young might be as a starting point for the construction of therapies to slow aging.
None of us was made from scratch. Every human being develops from the fusion of two cells, an egg and a sperm, that are the descendants of other cells. The lineage of cells that joins one generation to the next - called the germline - is, in a sense, immortal. Over time, a cell's proteins become deformed and clump together. When cells divide, they pass that damage to their descendants. Over millions of years, the germline ought to become too devastated to produce healthy new life. "You take humans - they age two, three or four decades, and then they have a baby that's brand new. There's some interesting biology there we just don't understand."
Researchers have now reported the discovery of one way in which the germline stays young. Right before an egg is fertilized, it is swept clean of deformed proteins in a dramatic burst of housecleaning. The researchers discovered this process by studying a tiny worm called Caenorhabditis elegans. Most C. elegans are hermaphrodites, producing both eggs and sperm. As the eggs mature, they travel down a tube, at the end of which they encounter sperm. Researchers discovered that a worm's eggs carry a surprisingly heavy burden of damaged proteins, even more than in the surrounding cells. But in eggs that were nearing the worm's sperm, the researchers found far less damage. These experiments raised the possibility that the sperm were sending out a signal that somehow prompted the eggs to rid themselves of damaged proteins.
The researchers then created mutant "female" worms and observed that their eggs all became littered with protein clumps. When the researchers let them mate with males, however, the clumps disappeared from the eggs. They then carried out additional studies, such as looking for other mutant worms that could not clear out protein clumps even though they could make sperm. Combining these findings, the researchers worked out the chain of events by which the eggs rejuvenate themselves.
It begins with a chemical signal released by the sperm, which triggers drastic changes in the egg. The protein clumps within the egg "start to dance around." The clumps come into contact with little bubbles called lysosomes, which extend fingerlike projections that pull the clumps inside. The sperm signal causes the lysosomes to become acidic. That change switches on the enzymes inside the lysosomes, allowing them to swiftly shred the clumps. Researchers hypothesize that the worms normally keep their eggs in a dormant state. The eggs accumulate a lot of damage, but make little effort to repair it. Only in the last minutes before fertilization do they destroy protein clumps and damaged proteins, so that their offspring won't inherit that burden.
"The hypothesis is that it's not just a worm thing." In their new paper, the researchers reported that they had tested this hypothesis on frogs, which are much more closely related to humans than is C. elegans. The scientists exposed frog eggs to a hormone that signals them to mature. The lysosomes in the frog eggs became acidic, just as happens in worms. The germline may not be the only place where cells restore themselves in this way. Throughout our lives, we maintain a supply of stem cells that can rejuvenate our skin, guts and brains. It may be that stem cells also use lysosomes to eradicate damaged proteins. It might be possible, for example, to treat diseases by giving aging tissues a signal to clean house.
Although individuals age and die with time, an animal species can continue indefinitely, because of its immortal germ-cell lineage. How the germline avoids transmitting damage from one generation to the next remains a fundamental question in biology. Here we identify a lysosomal switch that enhances germline proteostasis before fertilization. We find that Caenorhabditis elegans oocytes whose maturation is arrested by the absence of sperm exhibit hallmarks of proteostasis collapse, including protein aggregation. Remarkably, sperm-secreted hormones re-establish oocyte proteostasis once fertilization becomes imminent.
Key to this restoration is activation of the vacuolar H+-ATPase (V-ATPase), a proton pump that acidifies lysosomes. Sperm stimulate V-ATPase activity in oocytes by signalling the degradation of GLD-1, a translational repressor that blocks V-ATPase synthesis. Activated lysosomes, in turn, promote a metabolic shift that mobilizes protein aggregates for degradation, and reset proteostasis by enveloping and clearing the aggregates. Lysosome acidification also occurs during Xenopus oocyte maturation; thus, a lysosomal switch that enhances oocyte proteostasis in anticipation of fertilization may be conserved in other species.