3 ms·

Want to help the elderly? Then help with the logistics needed to get current first generation well-characterized senolytic drugs into widespread use. The failin

Want to help the elderly? Then help with the logistics needed to get current first generation well-characterized senolytic drugs into widespread use. The failing health of the elderly is the root of every challenge related to old age, and that failing health is driven by the fundamental causes of aging such as accumulation of senescent cells. To the degree that rejuvenation can be achieved with reliability and low cost, such as through these senolytic drugs, it should be a priority. The dasatinib + quercetin combination for clearance of senescent cells is an excellent candidate on the basis of cost, evidence, and amount of information on these compounds, as well as a clear, low-cost, legal path for companies to bring it to patients. The eventual size of the market is every human being much over the age of 50. 1) Senescent cell accumulation is one of the root causes of aging, supported by decades of scientific evidence [1]. In lab mice, removal of senescent cells has partially reversed progression of osteoarthritis, lung disease, kidney disease, tauopathies such as Alzheimer’s disease, and a long and growing list of other age-related conditions. 2) A single treatment of dasatinib + quercetin clears a fraction of senescent cells in aged mice, leading to lasting improvement in health as a result [2]. Monthly treatment of dasatinib + quercetin starting in late old age reverses measures of age-related decline and extends life by 36% in mice [3]. 3) Dasatinib is a generic chemotherapy drug, originally approved for the treatment of cancer in 2006 as Sprycel. Pharmacology and side-effects in humans are well characterized [4]. Quercetin is a widely used flavonoid supplement. Quercetin is not effective versus senescent cells when used on its own [5]. 4) The non-profit Betterhumans is running human trials of dasatinib + quercetin, as is the Kogod Center at the Mayo Clinic. 5) Dasatinib costs less than US$100 per dose if obtained from manufacturers, deriving a human dose from the mouse studies. Perhaps US$200 per dose in the form of Sprycel via the pharmaceutical market. Quercetin costs less than a dollar per dose. 6) A drug approved by the FDA for one use can be prescribed by physicians for other uses, if in their professional judgment it is safe and effective. This is known as off-label use, and is commonplace for many medications. [1]: https://doi.org/10.1111/j.1749-6632.2002.tb02115.x https://doi.org/10.1111/j.1749-6632.2002.tb02115.x [2]: https://doi.org/10.1111/acel.12344 https://doi.org/10.1111/acel.12344 [3]: https://doi.org/10.1038/s41591-018-0092-9 https://doi.org/10.1038/s41591-018-0092-9 [4]: https://doi.org/10.1124/dmd.107.018267 https://doi.org/10.1124/dmd.107.018267 [5]: https://doi.org/10.1371/journal.pone.0190374 https://doi.org/10.1371/journal.pone.0190374

fjsolwmv 8y ago
How many doses does a person need per year? What does "partially reversed" mean? What are the side effects?
- reasonattlm 8y ago
  Arguably one dose per year. Arguably several in close sequence, but still very intermittently, such as once a year. Senescent cells accumulate slowly, so there is no reason to dose frequently on an ongoing basis. Different mouse studies of dasatinib + quercetin used single doses or a few monthly doses in sequence. This is true of dasatinib, but varies for other chemotherapeutic senolytics. Bcl-2 inhibitor chemotherapeutics generally want a week or a few weeks of dosing, rather than a single dose, which is a compelling reason to avoid them until better versions come along. The FOXO4-DRI injected peptide was a single treatment of three doses over a week in mice. That again is probably once a year in humans until someone turns up with evidence to suggest otherwise. Validation of the above educated guess, and some form of dose optimization, will arrive sometime after the introduction of good senescence assays that don't involve staining tissue samples, something that isn't viable for everyday human medicine. As to what "partially reversed" means, the answer is "read the literature". It is all out there. Search PubMed for "senolytic". Use Sci-Hub to read papers. The comparison pictures of treated and untreated mice in papers that have them are particularly telling, but no substitute for the raw data on arthritis, cardiovascular function, inflammation, neural function, tissue elasticity, etc. For side effects, a single dose dasatinib pharmacokinetics study in volunteers with lots of references to start you off: https://doi.org/10.1124/dmd.107.018267 https://doi.org/10.1124/dmd.107.018267

fjsolwmv 8y ago

How many doses does a person need per year? What does "partially reversed" mean? What are the side effects?

reasonattlm 8y ago
Arguably one dose per year. Arguably several in close sequence, but still very intermittently, such as once a year. Senescent cells accumulate slowly, so there is no reason to dose frequently on an ongoing basis. Different mouse studies of dasatinib + quercetin used single doses or a few monthly doses in sequence. This is true of dasatinib, but varies for other chemotherapeutic senolytics. Bcl-2 inhibitor chemotherapeutics generally want a week or a few weeks of dosing, rather than a single dose, which is a compelling reason to avoid them until better versions come along. The FOXO4-DRI injected peptide was a single treatment of three doses over a week in mice. That again is probably once a year in humans until someone turns up with evidence to suggest otherwise. Validation of the above educated guess, and some form of dose optimization, will arrive sometime after the introduction of good senescence assays that don't involve staining tissue samples, something that isn't viable for everyday human medicine. As to what "partially reversed" means, the answer is "read the literature". It is all out there. Search PubMed for "senolytic". Use Sci-Hub to read papers. The comparison pictures of treated and untreated mice in papers that have them are particularly telling, but no substitute for the raw data on arthritis, cardiovascular function, inflammation, neural function, tissue elasticity, etc. For side effects, a single dose dasatinib pharmacokinetics study in volunteers with lots of references to start you off: https://doi.org/10.1124/dmd.107.018267 https://doi.org/10.1124/dmd.107.018267