Improved Quality Control of Protein Folding Extends Life in Nematode Worms
In the paper I'll point out today, researchers map an efficient form of protein quality control from stem cells and recreate it in somatic cells, producing extended life in nematode worms as a result. Proteins are large, complex molecules, and their correct function depends on the assumption of a precise three-dimensional arrangement after creation, a process known as protein folding. Proteins can and do misfold, however, and in doing so many become actively harmful rather than merely unwanted clutter. A baroque system of chaperone proteins assists in correct folding, as well as identification and removal of misfolded molecules. The presence of misfolded proteins is effectively a form of damage: some of the molecular waste that accumulates with age and contributes to the development of age-related disease consists of misfolded proteins, such as the various forms of amyloid, for example. The gradual failure of cellular recycling systems, such as declining lysosomal function caused by the presence of metabolic waste that is hard for the body to break down, or similar failures in the proteasome, also contribute to rising levels of damaged and dysfunctional proteins. Since aging is nothing more than the accumulation of damage and the reactions to that damage, more efficient operation of chaperone and other quality control systems in cells should slow aging: the less damage there is at any one time, the less of an opportunity that damage has to spread and cause secondary issues. It is probably not a coincidence that increased quality control activity is observed in many of the methods shown to modestly slow aging in laboratory animals, and that some forms of slowing aging cannot work without that quality control boost.
As for any study that extends life in short-lived species in this way, it is worth noting that the life span of short-lived species is far more plastic than that of longer-lived species such as we humans. Where the research community can directly compare methods, such as calorie restriction, exercise, or growth hormone receptor mutation, it is clear that doubling worm life spans or a 40-60% increase in mouse life spans certainly doesn't map to that much of a change in human life span - or even more than just a few years. If it did, we've have noticed by now, as it would leap out of the data on human health and mortality. That researchers don't see that in the data constrains the effects to be fairly small, a handful of years at most. So for my part I believe we should look at this and other similar studies as indicators of importance, not a literal guide to building human therapies. These studies help to point out which forms of age-related molecular damage have the biggest impact, and thus are the highest priority for repair via the methods outlined in the SENS rejuvenation research proposals. It isn't a suggestion to attempt to adopt modified chaperone systems in humans, as that would be a highly inefficient way to proceed. It would likely produce results on a par with exercise or calorie restriction: improved health, modestly slowed aging. That is far less useful than methods of repairing the damage, clearing out all of the misfolded proteins every now and again before they rise to the level of causing real issues. Periodic repair can create rejuvenation if comprehensive enough. In the near term of decades, adjusting biology to run in a different way can only modestly slow aging; it will be a long time indeed before the research community is capable of safely creating a new biology that doesn't age in this way. That is time far better spent on the faster path to working rejuvenation treatments.
Defining immortality of stem cells to identify novel anti-aging mechanisms
With age, somatic cells such as neurons lose their ability to maintain the quality of their protein content. Pluripotent stem cells, on the contrary, do not age and have increased mechanism to maintain the integrity of their proteins. The survival of an organism is linked to its ability to maintain the quality of the cellular proteins. A group of proteins called chaperones facilitate the folding of proteins and are essential to regulating the quality of the cellular protein content. This ability declines during the aging process, inducing the accumulation of damaged and misfolded proteins that can lead to cell death or malfunction. Several neurodegenerative age-related disorders such as Alzheimer's, Parkinson's or Huntington's disease are linked to a decline in protein quality control.
Human pluripotent stem cells can replicate indefinitely while maintaining their undifferentiated state and, therefore, are immortal in culture. This capacity necessarily demands avoidance of any imbalance in the integrity of their protein content. "There is one chaperone system, the TRiC/CCT-complex that is responsible for folding about 10% of all the cellular proteins. By studying how pluripotent stem cells maintain the quality of their proteome, we found that this complex is regulated by the subunit CCT8. Then, we discovered a way to increase the assembly and activity of the TRiC/CCT complex in somatic tissues by modulating this single subunit, CCT8. The increase resulted in prolonged lifespan and delay of age-related diseases of the model organism Caenorhabditis elegans. For this study we combined the results from human pluripotent stem cells and C. elegans, to have both in vitro and in vivo models, providing a more convincing approach. Our results show that expressing CCT8 as the key subunit of the complex is sufficient to boost the assembly of the whole system. It is very interesting that expressing this single subunit is enough to enhance protein quality and extend longevity, even in older animals. One of our next steps will be to test our findings in mice."
Human embryonic stem cells can replicate indefinitely while maintaining their undifferentiated state and, therefore, are immortal in culture. This capacity may demand avoidance of any imbalance in protein homeostasis (proteostasis) that would otherwise compromise stem cell identity. Here we show that human pluripotent stem cells exhibit enhanced assembly of the TRiC/CCT complex, a chaperonin that facilitates the folding of 10% of the proteome. We find that ectopic expression of a single subunit (CCT8) is sufficient to increase TRiC/CCT assembly. Moreover, increased TRiC/CCT complex is required to avoid aggregation of mutant Huntingtin protein. We further show that increased expression of CCT8 in somatic tissues extends Caenorhabditis elegans lifespan in a TRiC/CCT-dependent manner. Ectopic expression of CCT8 also ameliorates the age-associated demise of proteostasis and corrects proteostatic deficiencies in worm models of Huntington's disease. Our results suggest proteostasis is a common principle that links organismal longevity with hESC immortality.
I agree that interventions that modestly slow the rate of age-associated damage are not an efficient use of research money. That's because something like caloric restriction may be reducing oxidative damage accumulation from 10 units/day to 8 units/day in a best case scenario, not 0. But in pluripotent stem cell culture (or germ cells, outside the lab), the existing system actually does reduce damage accumulation over time to 0, at least in some lineage of the cells. At least some chaperones can promote degradation of misfolded proteins, so the actual damage accumulation over time may be negative. Copy-pasting that protein expression system into more differentiated stem cell populations that normally senesce + senescent cell clearance seems to me to be a viable strategy for rejuvenating many tissues.
That said, to the best of my knowledge all natural and man-made "immortal" cells are only immortal in the lineage sense. A single cell will eventually accumulate misfolded proteins and other damage and die, removing those proteins from the population. If we want to produce a functional neuron that lasts indefinitely, we need to develop rejuvenation techniques beyond the scope of those that exist in nature. I don't know if that is actually required though - perhaps periodic delivery of engineered neural progenitors or establishment of an engineered neural stem cell population is a better approach.