To go along with a few posts from last week, here is a longer report from this year's Rejuvenation Biotechnology conference, hosted by the SENS Research Foundation. There are some interesting tidbits in the section on thymus regeneration, which is an approach to immune system rejuvenation that promises to be very helpful, even if not capable of solving all of the problems of the aging immune system in and of itself. A sizable component of the frailty of aging arises because the immune system becomes dysregulated and incompetent, its complement of cells capable of destroying pathogens reduced to very low levels, replaced by other types of immune cell that do little to help in this situation. Regeneration of the thymus is one of a number of possible ways to introduce much larger numbers of fresh new immune cells into an old body, thereby patching this problem to at least an initial degree:
Georg Hollander presented a cogent and enlightening exegesis of the thymus, from basic function to ongoing projects. The thymus is a small gland under the breastbone that is responsible for a crucial function of the immune system: training white blood cells (T-cells) to distinguish between self and other, so they can consistently attack the latter and spare the former. In adulthood, the thymus atrophies ("thymic involution"), and in old age there is almost no thymus left, with the disastrous result that T-cells not only fail to protect our bodies from invaders, but treat our bodies as the enemy, leading to autoimmunity. The training is performed by web-like epithelial cells, shaped like crumpled blankets, each epithelial cell in contact with up to 60 developing T-cells. Epithelial cells must express every single protein in the genome, and there is a transcription factor called AIRE that binds to DNA, promoting "promiscuous expression." Curiously, AIRE works best for genes that are normally turned off by methylation or acetylation. 15% of genes are expressed only in the presence of AIRE. There are microRNAs that are also necessary for promiscuous expression of all genes.
Hollander has been working on the hypothesis that each epithelial cell succeeds in programming only a random subset of the genome, so if you have fewer epithelial cells late in life, the cells collectively will not express every single gene in the body; there will be holes in the set of all genes represented in the thymus, and as a result there will be autoimmunity. He said we need a minimum 200-300 epithelial cells for a fully-functioning thymus that protects the body against itself.
At Wake Forest Inst, John Jackson is working on growing epithelial cells in a petri dish, then forming them on a scaffold, integrating blood vessels (vascularization) and structural (stromal) cells. His intern Blake Johnson made remarkable progress in a single summer toward creating a functional mouse thymus. Mice (like other small animals) have much larger thymi in relation to body size; and (like humans), they lose most of their thymic volume over their short lifetimes, with the result that their immune systems are disabled and they are vulnerable especially to cancer.
FOXN1 may be a key to reactivating the tired thymus. Greg Fahy of 21st Century Medicine is conducting a tiny clinical trial in the coming year, using growth hormone and other blood factors to regrow the thymus in people 50-65 yo. (Enrollment is closed; they are not seeking test subjects.)
The author here is more or less on the other side of what I consider to be a very important divide in how best to approach longevity research. I'd separate the research world between those who want to alter the operation of metabolism to make the damage of aging accrue more slowly, which is roughly the current mainstream, and those who want to leave metabolism working exactly as it is but periodically repair the damage. I favor the latter approach, the author the former.
To me attempts to rebuild a new state for the operation of cellular metabolism, while ensuring it to be safe and effective, looks both very hard and very expensive. We can look back at the the vast sums of money and years of work poured into efforts to make some headway, and with very little to show for it other than a massive increase in the size of databases and the scope of what is yet to be understood. Metabolism is fantastically complicated. It is still the case that researchers cannot definitively explain how the most reliable intervention to slow aging actually works: a full accounting of how calorie restriction improves health and extends life still lies somewhere in the future. Billions of dollars have been spent on attempts to understand and replicate these effects, and yet even if successful a calorie restriction mimetic drug far better than all of the possible candidates touted today will still have only modest effects on human life span.
The repair approach on the other hand is unbounded in its potential benefits. Repair well enough and aging can be reversed or indefinitely postponed: your only limit is the effectiveness of the technology. This is still the disruptive minority interest in the field, but I predict that change lies ahead as research programs following this path produce much larger and more reliable benefits to health and longevity than are achieved through the traditional drug discovery process when applied to aging. We have seen the first steps on this path of late in the form of senescent cell clearance and progress towards clinical implementation of allotopic expression to work around mitochondrial DNA damage.
Obviously there are no clear cut lines in life, and grey areas abound in a field this complex. The author's terminology is useful, I think, though I differ on which path is the better one. It seems to me that some significant forms of damage in the aging body cannot be repaired by the biochemistry we have, no matter what signals we issue to change cell behavior, such as some forms of cross-link that degrade tissue structure and elasticity:
Very broadly, there are two approaches to anti-aging medicine, which might be called "bioengineering" and "endocrinology". The question is, how much of the change that takes place with age can the body reverse with its internal resources, given the appropriate chemical signals (that's endocrinology)? And how much remains that must be rebuilt or replaced with prosthetics (bioengineering)? From the beginning, SENS has emphasized the bioengineering approach - its middle name is "engineering". I am more optimistic about what the body might be able to do on its own, if only we can master its biochemical language.
Significant advances have been made in bioengineering in the 15 year history of SENS. A prosthetic limb no longer needs to be a peg leg, but can be designed to respond to neural signals. Prosthetic eyes and ears have come down from the clouds into the realm of the feasible. The first organs grown cell-by-cell on scaffolds in the lab have been re-implanted successfully in human patients.
But even more stunning and promising breakthroughs have appeared in the realm of chemical signaling. In 2000, before the Bush Ban, all stem cell research depended on embryonic stem cells harvested from foetal tissue; but turning muscle or skin cells back into stem cells has turned out to be surprisingly easy (though the process is still being refined). "Epigenetics" was an abstract noun in 2000, and it is now the fastest-growing area of biological science. Epigenetic signaling may be the organizing principle of whole-body aging. Signal proteins have been identified that turn on whole systems of genes that retard aging. Better yet, pathways that promote inflammation (e.g. TGF-β, NFkB) can be blocked, while some blood factors turn on regenerative pathways, with the promise of rejuvenation.