Fight Aging!

Salamander regeneration is becoming well studied. Researchers are mining the biochemistry of this and other proficient regenerator species such as zebrafish, as they would like to port over the ability to regrow limbs and internal organs into humans via the application of suitably designed medical biotechnology. At present it is an open question as to whether this a practical goal for the near future. While the past decade of investigation has uncovered a great deal of interesting new information on exactly how organ regeneration progresses in these species, it hasn't pulled out any one obvious manipulation that could be attempted in human biochemistry. So at this point making humans regrow lost limbs and organs in the same way that salamanders are capable of might prove be anything in between the extremes of (a) an enormously complicated reforging of our fundamental biochemistry better suited for the 2050s than the 2020s, and (b) something strikingly obvious in hindsight that could be implemented today were the details made clear. We just don't know yet.

On a completely separate topic, interest is picking up in senescent cells as a target for the treatment of aging. A demonstration of improved healthspan in mice through partial clearance of senescent cells was made public earlier this year, and that was the culmination of several years of murmurings following earlier, less compelling technology demonstrations. Several research teams are working on different methods of achieving the same end, at various very early stages on the road to readiness for clinical trials. Senescent cells contribute to aging in near every tissue: they accumulate over time in response to cell damage or a potentially damaging tissue environment, and not enough of them are destroyed by their own programmed cell death mechanisms or the watchful eye of the immune system, ever alert for errant cells that should be removed from the picture. Every senescent cell emits a cocktail of signal molecules that corrodes the nearby extracellular matrix and changes the behavior of surrounding cells for the worse. Enough of that and organ function declines into disease states.

Give these two contexts, this recent open access research is rather intriguing. It seems that salamander immune cells are exceedingly effective at destroying senescent cells during their regenerative process, and indeed at other times as well - which adds another mechanism that would be nice to port to humans if at all possible. Note that the full paper is PDF format only at this point, and so you'll have to click through to download and read it.

Recurrent turnover of senescent cells during regeneration of a complex structure

Cellular senescence has been recently linked to the promotion of age-related pathologies, including a decline in regenerative capacity. While such capacity deteriorates with age in mammals, it remains intact in species such as salamanders, which have an extensive repertoire of regeneration and can undergo multiple episodes through their lifespan. Here we show that, surprisingly, there is a significant induction of cellular senescence during salamander limb regeneration, but that rapid and effective mechanisms of senescent cell clearance operate in normal and regenerating tissues. Furthermore, the number of senescent cells does not increase upon repetitive amputation or ageing, in contrast to mammals.

It is clear that salamanders possess a rapid and efficient mechanism to recognise and clear senescent cells that either arise endogenously, or are introduced from culture. Our study demonstrates that a robust macrophage-dependent surveillance mechanism operates in normal and regenerating tissues of adult salamanders, and this allows them to circumvent the negative effects associated with the long-term accumulation of senescent cells, such as the disruption of tissue structure and function. These surveillance mechanisms are particularly significant for limb regeneration because there is a notable induction of cellular senescence during this process. Consistent with this, recent reports show that systemic macrophage depletion during salamander limb regeneration leads to defects in this process.

We propose that effective immunosurveillance of senescent cells in salamanders supports their ability to undergo regeneration throughout their lifespan. It has recently been suggested that targeting senescent cells could lead to therapeutic strategies for age-related pathologies. Here, we identify an animal with an efficient mechanism for surveillance of senescent cells operating through adulthood. Analysis of this mechanism could lead to the identification of novel therapeutic targets for the amelioration of age-related disorders and extension of healthspan.

There is a further interesting twist here. The occurrence of cellular senescence in aging may well be an evolutionary adaptation of its role in embryonic development, where it is thought to act as a guide in the development of tissue shape, such as at the tips of limbs and fingers. In this light, the greater presence of senescent cells during salamander regeneration might not be all that surprising: at the level of cellular organization regrowth of a limb acts in many ways like the embryonic development of that same limb. So is improved immune surveillance of senescent cells in salamander regeneration just the same thing that already happens in mammals during their embryonic development? Or is it something quite different, as indicated by the fact that it operates all the time and across a lifespan? These are not questions with definitive answers, and so, as for regeneration itself, further research is needed to understand whether or not greater immune clearance of senescent cells can be brought from salamander to human as a practical concern.