In this work, we surveyed 16 of the most extensively reported lifespan-extending compounds in C. elegans. We tested their effect on lifespan using two different types of food (live and UV-killed E. coli OP50). Moreover, we assessed the effect of the compounds on the bacteria itself, as well as their effect on lifespan of different nematode strains, and at multiple ages. In addition, we identified several new combinations of compounds with synergistic effect on lifespan. Importantly, we also showed that some of these compounds extend lifespan in D. melanogaster, demonstrating a conserved effect across species. Lastly, we opened our screen to a larger pool of compounds and identified novel lifespan-extending molecules in C. elegans.
It’s pretty interesting how MAO-B inhibitors like safinamide, selegiline, and rasagiline lead to so different results, the last two don’t seem to affect lifespan at all. None of them target LSD1, so it’s a bit of a mystery why their effects vary. This goes for tadalafil and sildenafil too. Maybe C. elegans isn’t the best choice for studying lifespan after all?
Safinamide is an inhibitor of monoamine oxidase B (MAO-B; IC50 = ~0.1 μM). It is selective for MAO-B over MAO-A (IC50 = >10 μM). It also inhibits radioligand binding to sodium channel binding site 2, sigma-1, and sigma-2 receptors in rat brain membranes (IC50s = 8.2, 0.019, and 1.59 μM, respectively).
Rasagiline is an inhibitor of monoamine oxidase B (MAO-B; IC50 = 4.43 nM for rat brain enzyme).1 It is selective for MAO-B over MAO-A (IC50 = 412 nM for rat brain enzyme). It inhibits serum and NGF withdrawal-induced apoptosis of PC12 cells when used at concentrations ranging from 0.01 to 100 µM.2 Rasagiline inhibits rat brain MAO-B in vivo (ED50 = 0.1 mg/kg).1 It reduces cerebral edema in a mouse model of traumatic brain injury.2 Rasagiline (0.1 mg/kg) reduces cortical and hippocampal levels of full-length and soluble amyloid precursor protein (APP) in rats and mice. It also reduces α-synuclein-induced substantia nigral neuron loss and improves motor dysfunction in a mouse model of Parkinson’s disease.3 Formulations containing rasagiline have been used in the treatment of Parkinson’s disease.
Monoamine oxidase (MAO) inhibitors have utility in ameliorating a variety of neurological conditions, including depression.1 R-(−)-Deprenyl is a selective, reversible inhibitor of MAO-B (Ki = 0.091 μM) over MAO-A (Ki = 9.06 μM).2,3 In addition to finding use against depression, R-(−)-deprenyl provides neuroprotection which may be relevant to Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, and stroke.4,1 The ability of this compound to slow the progression of disability in early Parkinson’s disease may be independent of its effects on MAO activity.4
It is almost the lowest-hanging fruit. I attach very little importance to C.elegan’s results.
Maybe C.elegan results should be used as a filter to determine which substances should be tested in mice or rats.
Here we developed a platform in a naturally short-lived vertebrate, the turquoise killifish, for the systematic exploration of aging and age-related diseases. The field of aging will greatly benefit from the study of species beyond conventional model systems (Bolker, 2012). Many exceptionally long-lived vertebrates, such as the naked mole rat (~30 years), the Brandt’s bat (~30 years), capuchin monkey (~50 years), rock fish (~150 years), and the bow-headed whale (~200 years) (Tacutu et al., 2013) have already allowed comparative genomics, proteomics, and cellular studies (Austad, 2010; Gorbunova et al., 2014). However, long-lived species are not well-suited for genetic manipulation, longitudinal, or lifespan studies. The turquoise killifish, with its naturally short lifespan, well-characterized aging traits, low costs, and ease of maintenance in the laboratory, is highly suited for rapid experimental aging research in vertebrates. Furthermore, the turquoise killifish is currently the shortest living vertebrate with a sequenced genome, which will be valuable for comparative studies.
Fish provide several advantages as laboratory species. They are amenable to high throughput approaches such as genetic and drug screens (Schartl, 2014). Fish also display a range of unique traits. For example, zebrafish, the primary fish model, is widely used for developmental processes due to its unique characteristics (e.g. fast and stereotypic embryonic development). Other fish have been used for specific traits, including social behaviors (cichlids (Fernald, 2012)) and adaptive evolution (sticklebacks (Jones et al., 2012)). Our genome and genome-editing platform in the turquoise killifish should help transition this fish to a more widely studied model, providing a unique opportunity for high throughput aging and longitudinal studies. It will be important to characterize aging in the mutants we have already generated as well as generating additional ones. Finally, the genome-to-phenotype platform we present here could serve as a paradigm for how to rapidly develop a wide range of species into model organisms.
The deep evolutionary conservation of basic vertebrate immune aging mechanisms shared between mammals and killifish positions these naturally short-lived vertebrates as a powerful platform for testing interventions that may prove effective across vertebrates, including humans. Killifish can be ideal experimental animals to test the impact of immune therapy in the context of aging and aging-related disease models. Building upon established interventions, killifish offer a valuable platform for evaluating the effects of dietary modifications, medications, microbiome manipulations, precise genome editing through CRISPR/Cas9 technology [51, 53], vaccines, and stem cell transplantations [64], in alleviating immune system aging and its associated health implications.
It looks like Urolithin A is doing the trick in killifish. Maybe we should fire off some emails and see if anyone’s thinking about setting up a killifish-focused program similar to the ITP. We need a rapid and reliable method to screen all the FDA-approved medications (and other drug libraries) for any life-extending benefits.
When I first read about this I sent a message to the Wormbot guys and suggested they expand to cover killifish also, but I suspect they have too much on their table already. But yes - an ITP-focused on killifish would be great.
Do you think Alex Zhavoronkov knows any rich guys from Asia or the Middle East who could fund it? He’s really into longevity, and AI isn’t enough on its own. I’m sure he knows about Rapamycin News and would appreciate an email. You could also interview him. He’s a brilliant guy.
Yes, that is a very interesting combo! I also sent in an order on that before I saw that you had also done it. I wonder how Ora handles duplicate orders. Maybe we can test different doses here. By the way, did you choose any specific doxycycline (Doxycycline Hcl or Doxycycline hyclate) or did you take both? I ordered combo experiments on both and also single experiments on both.
Here is also one interesting article about Doxycycline.
The researchers tested doxycycline 20 times, but it’d be interesting to see if doxycycline works every single time with Ora too. Are you taking Oracea (doxycycline XR)?
We further tested several of these compounds at multiple concentrations to determine if there was a dose-response effect. Indeed, caffeine and captopril did not extend lifespan at lower concentrations and minocycline had a reduced effect at higher concentrations. On the other hand, doxycycline extended lifespan at relatively low concentrations, up to and including 50uM.
Notably, we found that doxycycline extended C. elegans lifespan when administered at L4 and day 1 adult stages, regardless of diet and concentration tested.
Based on the study in the main post and the one I published I think the right way to go is to increase the dose to around 15uM for best effect. 10uM resulted in 25% median lifespan increase. 13uM resulted in 73% median lifespan increase but I think the control may be short lived. I need to dig more around that. What do you think about increasing the dose a bit instead? Even the mega dose (130uM, 64% increase in lifespan) showed good effect.
