Another New Senolytic Prodrug is Demonstrated to Reverse Frailty and Loss of Cognitive Function in Old Mice

Today's open access paper reports on the use of a prodrug senolytic strategy to reverse aspects of aging in mice via the selective destruction of senescent cells. A prodrug is a small molecule, usually innocuous, that can be converted into an active drug molecule by the action of specific proteins in the body. For example a drug can be made into a prodrug by the addition of further chemical structure that (a) renders it inert, and (b) is cleaved away by an enzyme inside cells. Ideally, the inactive prodrug is designed such that this conversion to an active drug molecule only takes place where and when the drug is needed.

Senescent cell accumulation with age is an important cause of age-related degeneration and disease. Senescent cells are characterized by high levels of β-Galactosidase, known as senescence-associated β-Galactosidase (SA-β-Gal). Since β-Galactosidase is an enzyme that cleaves glycosidic bonds, it is possible to turn many types of drug into prodrugs that only activate to meaningful levels inside senescent cells by attaching structures that will be removed by β-Galactosidase. Researchers have recently demonstrated that this can be done with the chemotherapeutic drug navitoclax. Navitoclax is the worst of the effective first generation senolytics: it certainly kills senescent cells, and is somewhat specific, but it also kills far too many other cells for comfort. It has significant and unpleasant side-effects, but when it is made into a prodrug, these problems go away.

One doesn't have to use senolytic drugs as a basis for the prodrug. The results below were obtained using a fairly generic cytotoxic chemotherapeutic drug. More or less any cell-killing drug will do, so long as (a) it can be made inert with a structure that will be cleaved away by β-Galactosidase, and (b) the difference in amount of β-Galactosidase between normal cells and senescent cells is enough to make the difference between too few drug molecules to produce any measurable effect and sufficient drug molecules to kill the cell.

Targeted senolytic prodrug is well tolerated and results in amelioration of frailty, muscle regeneration and cognitive functions in geriatric mice

Frailty is connected to cellular aging, which in turn is connected to cellular senescence. Senescent cells are permanently withdrawn from the cell cycle and generally develop a persistent pro-inflammatory phenotype called the senescence-associated secretory phenotype (SASP) which is comprised of proinflammatory cytokines and chemokines. Selective killing of senescent cells with therapeutics (i.e., senolytics) have gained attention as a new therapeutic approach for age-related diseases. Targeting of pro-survival Senescent Cell Anti-apoptotic Pathways (SCAPs) has emerged as the primary strategy for senescent cell killing.

The translational value of many senolytic drugs in vivo is limited due to their chronic toxicity. The identification of agents that selectively kill senescent cells while sparing other cell populations represents a scientific challenge. Current senolytic drugs target molecular pathways shared between senescent and proliferating cells, thus achieving cell killing but not specificity. As a matter of fact, many known senolytic agents were initially developed as cytotoxic anti-cancer agents and subsequently repurposed for 'selective' removal of senescent cell populations.

Senescent cells are characterized by a notable change in biological properties such as an increase in the levels of mitochondria, reactive oxygen species, lysosomal content, and upregulation of many lysosomal proteins, including the lysosomal enzyme senescence-associated β-galactosidase (SA-βGal). Recently, a promising strategy has been proposed based on galactose-derivative prodrugs. These prodrugs are selectively activated in senescent cells upon conversion into the parent active drug by the hydrolase activity of SA-βGal. In particular, specific senotoxic compounds such as duocarmycin, gemcitabine, and navitoclax have been modified into galacto-derivative prodrugs showing increased selectivity in targeting senescence cells and efficacy in treating cancer and aged mouse models.

Here, we report a novel prodrug design to target senescent cells, allowing systemic removal of senescent cells in geriatric mice without noticeable side effects. We took advantage of the senescence-specific activity of SA-βGal in the design of a non-toxic senolytic prodrug derivative of the compound 5-Fluorouridine, a metabolic precursor of the clinically approved anti-cancer medication 5-Fluorouracil. We first tested the specificity of this prodrug on senescent cells in vitro. We then confirmed safety and efficacy of the prodrug in young (5 month-old), aged (22 month old) and in geriatric (30 month old) mice. Importantly, we showed that geriatric mice that received the prodrug treatment for four weeks altogether improved significantly: 1) frailty profile; 2) skeletal muscle function; 3) muscle stem cell function; 4) cognitive function; and 5) survival.

Comments

It is very interesting, just yesterday i was lamenting that there are no senolytic prodrug studies and here we go. We are officially in the second generation of senolytics. I would put OISIN aside since their approach is quite different.

I think that most of the senolytic payload should be targeting the pathways that let the cells avoid apoptosis. That would reduce off-target toxicity in case there are other Galactosidase uses in "good" non-senescent cells.

Of course only studies and clinical trials will show what is the optimal approach.

Posted by: cuberat at October 28th, 2020 5:34 PM

Now is there a way i can get such progdugs.... Asking for a friend :)

Posted by: cuberat at October 28th, 2020 5:34 PM

Yea sure Cuberat. If I remember correctly, you are too young for this to have much effect on you:) You should be so lucky, I OTOH would/could use it.

Posted by: Robert at October 28th, 2020 6:33 PM

@Robert
Either I was to young or the fisetin batch I have got was working

Posted by: Cuberat at October 28th, 2020 7:22 PM

this is very exciting. I recently followed a great lecture on this work at Ending Age-Related Diseases 2020 conference, given by the senior corresponding author of this paper Dr. Marco Quarta (co-founder and CEO of Rubedo Life Sciences).

I remember him mentioning that the prodrug presented in this paper is an early proof of principle that they investigated years go. However, he then said that they are currently developing more sophisticated and selective senolytic prodrugs at the company. This is something they also mention in the paper, if you read the conclusions.

I look forward to seeing the future drug and clinical development around this concept, very promising!

Posted by: David at October 29th, 2020 2:37 PM

@David
So when cold we expect a candidate for human trials? I have two parents, in laws and I am not getting any younger.

Posted by: Cuberat at October 29th, 2020 6:19 PM

I wonder what the potential market size would be for a version of 5FURGal Prodrug produced via contract overseas and then sold illegally via the internet? Would someone be able to thumb their nose at the law and not personally lose a lot of money on every sale in the interests of making this wdiely available to people out there who are suffering right now (e.g. with knee pain due to senescence related osteoarthiritis)?

How could someone prove that the drug they had manufactured was the real deal?

How much would it cost for them to run a lifepsan experiment with Killifish instead of mice?

If someone could do all that then I personally would be interested in buying some.

Posted by: jimofoz at October 31st, 2020 2:00 AM

@ Cuberat
I have no idea, we should ask to Rubedo Life Sciences' folks. I wish I knew, but I hope soon! They seem to be moving fast though

Posted by: David at November 2nd, 2020 1:11 PM

This is quite interesting because of all the creams, lasers, treatments for skin aging, Ive seen nothing work better than 5fu. Specifically through a protocol developed by Dr. Katz in New York over 20 years ago called a Pulse peel. The results are obvious. His protocol prevents the peeling side effects. Far cheaper than thermage , chemical peels, microdermabrasion, microneedling,IPL, PRP, exosomes, cryotherapy, etc......it offered me superior results and Ive done them all. The news that 5fu is a senolytic explains a lot. Unfortunately few practices offer it. Dr. katz will share his protocol with any dermatologist, all they gave to do is ask. He also outlines it on youtube. The above treatments turn back the click maybe 5 years. The pulse peel series took my 40 year old skin back to 20.
This was all topical, I look forward to finding an intravenous doctor.

Posted by: august33 at November 2nd, 2020 9:58 PM

Post a comment; thoughtful, considered opinions are valued. New comments can be edited for a few minutes following submission. Comments incorporating ad hominem attacks, advertising, and other forms of inappropriate behavior are likely to be deleted.

Note that there is a comment feed for those who like to keep up with conversations.