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Why an immune system-focused prize
NickOttens
Posts: 899 admin
Human experiments can only be done legally in the form of clinical trials.
Phase 1 clinical trials are small and unconvincing, but still expensive.
Phase 2 clinical trials suffer from:
Finally, COVID-19 currently receives all the attention, and public and FDA resources are being rerouted to find solutions for the pandemic.
An immune system-focused XPRIZE Age Reversal mitigates some of these problems:
Phase 1 clinical trials are small and unconvincing, but still expensive.
Phase 2 clinical trials suffer from:
- High costs ($10-20 million for a novel compound) favor established firms and will most likely exclude newcomers.
- Firms may be reluctant to go into Phase 2 clinical trials. The FDA doesn't recognize aging as a disease, so there may not be a market for an age-reversal intervention.
- Risk of the patients suffering serious adverse events.
- Long timeframes. Novel interventions require pre-clinical trials, toxicity trials, and Phase 1 clinical trials before getting to Phase 2 clinical trials.
Finally, COVID-19 currently receives all the attention, and public and FDA resources are being rerouted to find solutions for the pandemic.
An immune system-focused XPRIZE Age Reversal mitigates some of these problems:
- We can reduce costs.
- There would be an immediate and highly profitable market for successful competitors' products, with accelerated trials.
- It would still achieve age reversal, as competitors would be required both to rejuvenate the immune system and decrease patients' biological age according to another composite biomarker (most likely epigenetic clocks). Treatments would therefore have to have a holistic impact on the body.
- There is a clear and well-understood need to vaccinate the elderly against COVID-19, which requires a functioning immune system.
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@JoseCordeiro, @ynevies, @celinehh, @dr2tom, @dai_andrew, I'd like to ask your opinion on this prize idea as well. Do you think it makes sense to focus on rejuvenating the immune system for a longevity XPRIZE? Or would you suggest looking at the cardiovascular system? Or the brain?
We're exploring the possibility of focusing an age-reversal XPRIZE on the rejuvenation of the immune system. If you have feedback, or alternative ideas, we'd love to hear it!
Arguments against include:
@dives86, @ErnieRogers, @Jozef, @markjayct, @aaroncp1an0, @DidierC, @davidsinclair, what do you think? Should we shift priorities? Make rejuvenation of the immune system one track in the prize and add, for example, the cardiovascular system and the brain? Or should we move away from the immune system altogether?
Improved immune competence would be tied to youthfulness, and when such outcomes are supported by rejuvenation of other systems (cardiovascular, brain, skin, epigenetic clocks), then together it could be indicative of age reversal.
Forgive me jumping into the middle of this discussion (although I had contributed ideas for Aging biomarkers, going back several months, on the relevant forum topic).
First, there is a connection between immune system health and cardiovascular disease (CVD) [K. Lavine, Washington University School of Medicine, 2018] via 'clonal hematopoiesis' (CH), sometimes also referred to as 'clonal hematopoiesis of indeterminate potential' (CHIP), a condition -- strongly associated with aging and disease -- in which somatic mutations in specific lineages of (bone-marrow derived) blood cells (known as Hematopoietic Stem Cells, HSCs) increase in frequency ('clonal expansion') and come to predominate within that blood cell population. [note: CH of lymphocyctes results in various forms of (often chronic) Leukemia]
Specifically, Lavine finds that a loss of function mutation in the myeloid cell gene that codes for the protein TET2 (an epigenetic driver*) triggers/activates the NLRP3 inflammasome and IL-1B production. These types of mutations (in HSCs, frequently in a single gene of one cell type) tend to accumulate with age and may offer a mechanistic explanation for why aging and disease are associated with inflammation -- and the often concomitant cardiovascular diseases, such as venal thrombosis, stroke, MI, etc.).
*Most mutation-driven cases of CH in humans are the result of mutations in epigenetic regulator genes (e.g., DNMT3A, TET2, others) commonly in immune cell types like monocytes, macrophages, granulocytes, and lymphocytes -- immune cells found throughout the body in nearly every tissue type.
Now, most somatic mutations (whether in HSCs or some other tissue cell type) do not confer a 'fitness advantage' and so they are eliminated (e.g., via the DDR). However, there is accumulating evidence (S. Jaiswal and Ebert, 2019) that on rare occasions, some of these mutations that evolve into CH/CHIP are under positive selection and provide a growth advantage to these (clonal) cell populations (which may be viewed, in the evolutionary context, as a cell population in competition with other cell populations). This 'rare mutational process' (i.e., rare in the young) occurs in many tissue types and becomes less and less rare as we age (between 10 and 20% of those older than age 70 harbor a clonal myeloid population of appreciable size).
In their research, Jaiswal and Ebert also cite recent studies that suggest that CHIP is associated with an increased risk of all-cause mortality and an increased risk of cardiovascular diseases (see those noted, above).
In evolutionary terms, if an organism (or cell type) is under positive selection (resulting in clonal expansion) and which confers a 'growth advantage', etc. it is a truism that stopping this selection (and the age-relate illness/condition) requires removing the 'agent of selection'. Therefore, the goal, in general, is to first identify the specific agent of selection (and target it for mitigation, or, elimination).
Now, 'immune system' is a broad term (as is 'immune competence') and refers to a great number of cell types, interactions (e.g., B cell-T cell coupling), processes, and conditions. So, it is important to reduce/refine our quest to a more specific immune system phenomenon (even if it is broadly manifested) or process. Here, I am suggesting that 'clonal hematopoiesis' or clonal expansion (of an identified cell type) would seem to be a valid, specific, and clear immune system 'target condition'.
Alternatively, or, in parallel to this search, the researchers emphasize the need to "develop strategies aimed at mitigating the adverse consequences of CHIP, such as lifestyle modifications or drugs that lower the risk of hematologic cancer and heart disease."
So, more concretely (as far as Jaiswal and Ebert's 'mitigation strategy')...I suggest here an obvious approach: that one of these strategies be the repairing of the mutation (in the epigenetic 'driver gene') that is fueling the positive selection of the clonal population (whether or not we can identify the actual selective agent) -- along with adjunct therapies to reduce inflammation (e.g., perhaps target/bind the cell surface receptor-ligand complex that triggers the inflammatory cascade, or block the production of the NLRP3 complex in vivo, etc.). This could be achieved via new (nucleotide) base editing technologies (e.g., sgCRISPR or shRNA cassettes, delivered to tissue cell types by next gen AAVs) -- performed in vivo first (ethically/humanely) in monkeys (as phase I/II) -- with the goal being the the (validated) significant decline, or complete elimination, of the clonal (e.g., myeloid cell type) population as the clear 'age reversal' indicator/benchmark.