Why an immune system-focused prize

NickOttensNickOttens Community ManagerBarcelona, SpainPosts: 851 admin
edited August 6 in Immune System Focus
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:
  • 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.

Comments

  • NickOttensNickOttens Community Manager Barcelona, SpainPosts: 851 admin
    @danbelsky, @barryflanary, @techspeaker, @dives86, @sureshj, @Steve_Liebich, what do you think about this approach? Does it make sense to you to focus an XPRIZE Age Reversal on the immune system? And/or should we consider the cardiovascular system? Or the brain?
  • dives86dives86 Posts: 5
    edited August 7
    I think its a good approach. As a guide, resTORbio recently pivoted their Rapalog RTB101 towards Cov19, as a prophylactic to reduce Cov19 severity in nursing home residents https://bit.ly/3im0Aoy
  • NickOttensNickOttens Community Manager Barcelona, SpainPosts: 851 admin
    Thank you for your feedback, @dives86!

    @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?
  • JoseCordeiroJoseCordeiro Madrid, SpainPosts: 5
    @NickOttens @Roey @Sergey1 @ynevies @celinehh @dr2tom @dai_andrew I think this would be a great initiative. The recent work from people like Greg Fahy and now also Reason! show that immuno-rejuvenation is possible and close at hand... let´s turn this Covid19 crisis into a longevity opportunity and a New Renaissance... https://lifeboat.com/ex/a.new.renaissance
  • NickOttensNickOttens Community Manager Barcelona, SpainPosts: 851 admin
    @siimsaare, @Ted, @JeffQuintero, I'd like to ask your opinion on this potential prize direction as well. Do you think it makes sense to focus a longevity XPRIZE on the rejuvenation of the immune system?
  • NickOttensNickOttens Community Manager Barcelona, SpainPosts: 851 admin
    @Liz_Parrish, @NickPineault, @joannabensz, @tblue, you may be interested in this discussion as well.

    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!
  • NickOttensNickOttens Community Manager Barcelona, SpainPosts: 851 admin
    We continue to debate whether or not to focus this prize on rejuvenation of the immune system, and would appreciate your advice.

    Arguments against include:
    • Excludes teams and technologies that do not focus on the immune system, including novel technologies that often have first indications relating to niche parts of the body.
    • Regulators may be more likely to approve localized approaches/therapies, as opposed to systemic therapies, especially for novel, more risky approaches.
    • The immune system is highly intricate and complex. This makes it difficult to impact/reprogram it in the right way. The immune system reaches almost every part in the body. Many auto-immune diseases are the result of a delicate balance being slightly off. We don't know how a rejuvenated (or invigorated) immune system would interact with an old body.
    • Jumping on the COVID bandwagon could prove counterproductive if a vaccine is developed before an age reversal prize can be funded and launched.

    @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?
  • dives86dives86 Posts: 5
    @NickOttens how do you plan to quantify rejuvenation for the Xprize? (since this sets constraints). Say you used DNAm GrimAge as a readout, its specialised to provide time to death, time to heart-disease and time to cancer predictions. GrimAge is also blood based, meaning teams must affect systemic ageing or target a niche part of the body whose rejuvenation has systemic impact (thymus regeneration in the TRIMM trial). It might be worth answering this question then working backwards?
  • NickOttensNickOttens Community Manager Barcelona, SpainPosts: 851 admin
    That's a good point. We've discussed relevant biomarkers to an immune system focus -- but none of them are perfect. Could we test immune system rejuvenation via the level of immune competence?

    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.
  • dives86dives86 Posts: 5
    NickOttens wrote: »
    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.
    Exactly - you want to see 1) functional rejuvenation, such as immune competence 2) rejuvenation in a core ageing biomarker (e.g. epigenetic age), suggesting future persistence of that functional rejuvenation. The latter offers a core track in the prize, the former a specialist track.
  • NickOttensNickOttens Community Manager Barcelona, SpainPosts: 851 admin
    @henry_bro, @akhachat, @stuartcalimport, @Wei, can I ask your opinion on this question too? It is wise to focus on rejuvenation of the immune system in an age reversal prize? Or should we prioritize a different system of the body?
  • marz62marz62 Seattle, WAPosts: 122 ✭✭✭
    edited September 16
    [In regards to 'immune competence' and the relationship between the immune system and heart health]

    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.

  • walticularwalticular Posts: 7
    I oppose narrowing the focus to immune system restoration. Immune system rejuvenation will not happen in isolation, in any case. Besides that, attempts to ride the coattails of the COVID19 epidemic are not likely to be effective, given the extraordinary political tilt of "science-based" decisions that we have witnessed, from which rejuvenation biotech has been excluded by silence. Note that none of the leading public figures have emphasized system-wide rejuvenation as the only long-term solution, even as it stares them in the face. This is not an accident or due to low IQs. The prize should focus on systemic rejuvenation and preventive therapy that begins early in life. Hold the high ground!
  • ymedanymedan Posts: 113 ✭✭
    edited September 18
    The immune system is triggerd by danger/emergengy signals. Hence, it is a downstream system rather than a source. I would therefore look for upstream signalling systems, two of which are the mitochondria and microbiome. Rejuvenating these will yield significant, immediate benefits (as is the case with fecal transplant and Mitochondria Augmentation Therapy)
  • SamLeTardifSamLeTardif Mr. Posts: 3
    edited September 21
    The goal of the prize should be to reverse the processes associated with aging. A strong immune system is just a side effect of a body not yet severely damaged by aging and nothing has shown this more dramatically than COVID-19. This immune system rejuvenation should be a major selling point to get the public on board, but it shouldn't be the ultimate goal of the prize.
  • NickOttensNickOttens Community Manager Barcelona, SpainPosts: 851 admin
    @Jolly_Bones, @ymedan, @walticular, @marz62, thank you for your feedback! It has helped us decide that we should go with a whole-body approach to age reversal. We'll have more details for you seen! Keep an eye on the forum and the newsletter.
  • marz62marz62 Seattle, WAPosts: 122 ✭✭✭
    The notion that the immune system is somehow "secondary" (or "downstream") to other (physiological) systems (presumably, ones constituting some 'Age-ome') is unfounded by current science. Immune cells play a fundamental role during in utero morphogenesis and a key role in Aging (see my post, above)...No 'age-reversal' solution will arise, in my opinion, without an inclusive role for the immune system (whether innate, adaptive, or both, or, a subset of immune cells used as a bio-marker of age-reversal). This includes brain-centered solutions (e.g., the prevention or reversal of AD [or amyloid-Beta protein, Tau protein, synuclein disorders]), of which the constituting neural cell types are nearly all supported, maintained, modified and/or 'pruned' by endogenous immune cells [glial cells, of various kinds]...and throughout the body, immune cells are coupled to nerve cells in complex.
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