One of the Ways Researchers Narrow the Search for Drugs to Slow Aging

Small molecule and drug candidate libraries are huge. Much of modern medical research is a process of screening subsets of those libraries in search of molecules that can produce benefits with minimal side-effects. Usually the output of a successful screen is taken as a starting point for further exploration and molecular tinkering, to improve the effect or minimize undesirable side-effects. The great hope for gene therapy is that it will render all of this largely obsolete by offering ways to directly influence a molecular mechanism to a configurable degree without meaningful side-effects. That remains a way off in the future, however, and meanwhile a very sizable slice of medical research is still all about finding which cataloged molecules might be interesting to work with.

Thus when it comes to aging, a majority of efforts are focused on adjusting the operation of metabolism via small molecules from the catalogs, interacting with one of the known aging-related mechanisms discovered via examination of the biology of calorie restriction, or autophagy, or other stress response mechanisms. This is somewhat depressing: none of this work offers either hope or possibility of doing more than slightly increasing human life span, yet it is where most the funding and effort is focused. An increasing fraction of those initiatives are concerned with ways to speed up this process, to make it more rational, to cut down the number of molecules to be assessed. These advances are interesting to the degree that they can be applied more generally, to any area of development. There are parts of the SENS rejuvenation research portfolio in which small molecule drug discovery might lead to useful therapies, for example.

Several bioinformatic methods have been developed to identify potential geroprotective drugs. For instance, caloric restriction (CR) mimetics have been identified, by comparing genes differentially expressed in rat cells exposed to serum from CR rats and rhesus monkeys with gene expression changes caused by drugs in cancer cell lines. Structural and sequence information on ageing-related proteins have been combined with experimental binding affinity and bioavailability data to rank chemicals by their likelihood of modulating ageing in the worm Caenorhabditis elegans and the fruit fly Drosophila melanogaster. Drug-protein interaction information has also been used to predict novel pro-longevity drugs for C. elegans, using a set of effective and ineffective lifespan-extending compounds and a list of ageing-related genes. A similar approach used chemical descriptors of ageing-related compounds from the DrugAge database together with gene ontology terms related to the drug targets. Enrichment of drug targets has been assessed for a set of human orthologs of genes modulating longevity in animal models to identify new anti-ageing candidates.

Despite the increasing interest in drug-repurposing for human ageing, research has tended to focus on predicting life-extending drugs for animal models. However, the translation from non-mammalian species to humans is still a challenge, and certain aspects of ageing may be human-specific. Only a few studies have focused on data from humans. For instance, researchers applied the GeroScope algorithm to identify drugs mimicking the signalome of young human subjects based on differential expression of genes in signalling pathways involved in the ageing process. Another study correlated a set of genes up- and down-regulated with age in the human brain with drug-mediated gene expression changes in cell lines from the Connectivity Map.

In the present study, we rank-ordered drugs according to their probability of affecting ageing, by measuring whether they targeted more genes related to human ageing than expected by chance, by calculating the statistical significance of the overlap between the targets of each drug and a list of human ageing-related genes. Additionally, to enhance the power of the approach, we mapped the drugs' gene targets and ageing-related genes to pathways, gene ontology terms, and protein-protein interactions, and repeated the analysis. We found that, independently of the data source used, the analysis resulted in a list of drugs significantly enriched for compounds previously shown to extend lifespan in laboratory animals. We integrated the results of seven ranked lists of drugs, calculated using the different data sources, into a single list, and we experimentally validated the top compound, tanespimycin, an HSP-90 inhibitor, as a novel pro-longevity drug.

Link: https://doi.org/10.1371/journal.pcbi.1006639

Comments

Death scares me to death.

Posted by: Gekki at January 18th, 2019 12:21 PM

@Gekki
Well put :o)
Although for me it's the long and painful road of torture towards death that scares me most.

Posted by: Thomas at January 18th, 2019 1:09 PM

Small molecule development will be useful in the areas of senolytics and cross link breaking, but the rest of the SENS portfolio would require more complex interventions

And all "rational" drug discovery has ever done is speed up the front end a bit - but that only a small % of the total work

Posted by: David Permisov at January 18th, 2019 1:30 PM

Hi ! Just a 2 cents.

Death scares me to Life/Live (that, much). Not afraid of living (to the point of, if so much, dying of it), but rather, afraid of dying, because living, (connected) both go together, can't remove former when 'doing' latter. People busy at living, then one day busy at dying, slowly or instantly. In any case, you would prefer the former, because I was very much in the latter but I had to become busy at the former again (reverse near-death/assured dying (-only-unassured-when-you-get-busy-living)).

BTW On another not These billionaires whom died recently, it's sad beyond words, espeically that one leaving 49 trillion fortune (with a T/trillion$) representing the investors/financiers, not just a billionaire, a trillionaire - now, gone. When you let it sink in you for a second, you need to get busy living and busy at dying, or busy at dying sick'rich. What does 49 trillion good do if people still age and die, including that one whom contributed such incredible wealth; it means that even trillionaires still are not impressed yet (so am I but I believe that 1 trillion or 2 could have 'helped' a bit the rejuvenuation field and not 'hurt too much' pockets; dead is dead; rich or not. When you realize that, then you realize that money is not all there is to it in life, life is more important, money makes you live and could even gain us LEV, but with peoeple garding their pretty trillions not happening until they are old and look self in mirror 'too late' 'shoulda spent my trillions' ...like on not dying, and when I was 'still young and was becoming rich'). Rich dead hero, still, *dead; hero (if I were trillionaire, it'S liek I would feel ashamed for having somuch cash while beggars lived by on 15cents a day....I would look at them and see myself, guilt ladden/I worked hard/but now I have it so east, long ago, as I too was poor, destitute, just with my life, just as I facwe when I nearly died, at the end of the day, all you have left, is you/your body/your life...your trillions are just taht, financial resources, pennies, nothing more, if you don't 'use/spend' them wisely instead of collecting them à la uncle ebenezer scrooge penny pincher mooch (and I,m not saying huge investors don'T give, they give plenty, but it'S not enough; you have to Want to defeat aging - you goot cash, tonsacash, make it happen....only, they (mostly) Want to get rich..and die, of it/accept this defeath, because they believe all is snake oil bs or nothing is working right now; probably think SENS is bs too (some truth there) but at least has some fundementals proven in science (proven is strong word, let's say, there is solid studies showing that we can reverse aging, but people keeping all this cash should almost be outlawed/like after your first trillion, each subsequent trillion you make, you give it to curing death, otherwise you are stripped of such faraminous/astronomical income or you are forced to leave 'society as citizen' and live in the woods or something/away from society (and astronomically disproportional rich compared from poor people on street, they billionaire matter too and yes you pay 500 bilion of taxes, but so what, left with so much more, Still even after that and having paid gigasums of taxes: capitalism success and failure at same time. Each one gets a chance to pot of gold, if not, poor, you die, too bad, so get rich or die quick(er). When you use money as resources as it has happen in last 1000 years, it's when sh*t happened (we shall put a price tag on everything and anything, soon maybe on Life and Death...wait a minute...it's already happening). Just a (more philo tangent 'I am Therefore I shall Get Busy Living, or Dying if Am Not (Alive, Still) Rich or Not') 2 cents.

Posted by: CANanonymity at January 18th, 2019 5:50 PM

PS: For many (rich & materialistic), Money > Life
(they won't give to SENS or other rejuvenation, they wanna keep their dough/they 'live' to make cash, rather than cash making them live (cash should never make you live/but alas it does in our societies tax/pricing everything)...and they don't mind aging all that much, only if SENS can rejuvenate a mouse to live much longer, will they give billions and be convinced. They want 100% assurance that their investment is not lost and will 100% reverse aging, otherwise they keep dough, and that is the problem; aging is stlightly more complicated than they thought, hence why it takes trillions to defeat it and 'its a gamble' just like life/death...not some iron-clad investment ROI - you are gambling on your life keeping such money).

For us, Money < Life.

Money = Life ?... Nah

Money = \ = Life. Life = invaluable/can't put a price tag. Sadly, for too many, you can (like in the old days of slavery: 'you are woth 'this much' and I own you 'for this much' - as if myself I was worth 'this much' (like when you here, oh this investor is 'worth this much' he/she is a 'billionaire' 'worth a billion'...his/her financial capacity yes - his/her life - No. Never.; 1 cent or 1 infinite quadrillion, life is invaluable 'by financial resource' mean).

Posted by: CANanonymity at January 18th, 2019 6:28 PM

PPS: (in french we say : 'crache le cash' (spit out your money, instead of keeping it like precious saliva. 'Saliva is Not Cheap..you know, soon we'll tax your saliva/50cents a ml tag)).

Posted by: CANanonymity at January 18th, 2019 6:46 PM

PPPS: and before someone says 'but what about you, give a lot to SENS or just cheap talk(er)?', I wish I could give more of course being so poort already but if, like many, making more it would be normal I would give because I would have more than sufficiency, as such would not put life at risk/living paycheque to paycheque, I also give other things (like children's fondation or cancer research (so many died of cancer in my family) but it's like I don't want to give to cancer research for having just a few dollars, they must go to the most important pressing matter - life/death, I want to give to cure death/aging - Which Will Cure Cancer too, And, death.

Posted by: CANanonymity at January 18th, 2019 6:52 PM

I view that for the foreseeable future it will still be small molecule drugs that deliver the results in anti-aging medicine.

Small molecules can do most everything luckily. Like say an older person has the stem cells declining in activity, and we wanted more stem cells in there replenishing the cell populations of organs. But for the sake of argument let us say stem cell therapies are not yet ready. Well small molecules can hypothetically be designed to upregulate the stem cell activity in those organs.

Another example of possibilities, is during 2018 the idea of 'circulating youth factors' in the blood of young mice emerged. What we want to do is narrow down what exactly those factors are, and then to develop drugs to upregulate production of those factors. Ideally if it is one factor, or at least a few factors that can be triggered by some cascade that can be targeted by small molecule drugs.

Posted by: aa3 at January 19th, 2019 1:57 AM

but, wait - there's more:
"Inhibition of Hsp90 stimulates the release of HSF-1, which in turn translocates to the nucleus, promoting transcription of HSPs [21, 25]. Increased levels of Hsp70 and Hsp90 have shown to be inversely proportional to β-amyloid and tau aggregation, and directly proportional to the binding of tau to microtubules, suggesting that inhibition of Hsp90 could serve as a neuroprotective approach for the treatment of Alzheimer's disease through dissolution of protein aggregates [22]."
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2659174/

Obviously, I have some reading to do...

Posted by: CD at January 19th, 2019 7:26 AM

Possibly small molecules research will impact in-vivo epigenetics reprogramming. I think we should watch closely also that space. Belmonte, Ocampo and many others are working in that direction with the vision epigenetics is centric between all the other 8 hallmarks. It might be far from the clinic though and I understand the "repair" mantra but progresses are being made fast.

Posted by: albedo at January 20th, 2019 9:57 AM

The frustrating thing is that when a promising small molecular is off-patent (e.g., MCC950) or close to being off-patent, as is tanespimycin, no one wants to pay for trials.

Posted by: CD at January 21st, 2019 10:21 AM

correction: tanespimycin went off-patent in 2014

Posted by: CD at January 21st, 2019 10:50 AM

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