A Profile of Buck Institute Startup Company Gerostate Alpha

A sizable fraction of the startup biotech companies in the small but growing longevity industry are essentially screening programs, in that they are developing various improvements on the standard approaches to screening small molecule databases in search of drugs that affect mechanisms relevant to aging. Some of them intend to take the best results from their screens into clinical development, while others intend to provide infrastructure drug development services, such as better, faster, or cheaper compound discovery and early validation, to the broader biotech industry. Examples among the first generation of longevity industry biotech startups include In Silico Medicine, BioAge, and Gero, among others.

Today's articles profile Gerostate Alpha, a more recently formed company that is incubated at the Buck Institute for Research on Aging, benefiting from the science and infrastructure there. The founders are most interested in entirely unbiased screening for compounds that slow aging and extend healthy life span, and less interested in a focus on any specific theory of aging or set of mechanisms. In the bigger picture, this is a useful exercise with a small chance of turning up interesting mechanisms involved in the progression of aging that have been overlooked.

That said, based on the results from other screening efforts, it is reasonable to believe that the vast majority of the output of the Gerostate Alpha screening process, meaning compounds that slow aging in short-lived species, will be those that upregulate stress response mechanisms, akin to those triggered by calorie restriction, and will thus have much smaller and less reliable effects in long-lived species. Whether there are specks of gold to be found amidst that low value dross is a question that can only be answered by a lot more unbiased screening than has so far taken place.

This low ratio of useful to entirely mediocre mechanisms and modulators of aging is the reason why I'm less in favor of unbiased screening than in the entirely biased approach of repairing the forms of cell and tissue damage known to be at the root of aging. That entirely biased strategy gave us senolytics, treatments that robustly produce rejuvenation in animal models by clearing senescent cells. There are a wide range of other forms of damage to be repaired, and an expectation that every one of them could turn out to be as good a field as senolytics. Aging is caused by damage. The best way forward is deliberate, targeted, periodic repair of that damage.

Gerostate Alpha: "The major modulators of aging remain to be discovered"

While many companies in Longevity are focused on addressing one or more of the hallmarks, or pillars, of aging, the founders of Gerostate Alpha always saw things a little differently. "People take the hallmarks of aging as a launching off point, thinking that if they can forestall a particular pillar, let's say inflammation, then they'll get beneficial outcomes - but this is a biased approach. We've always been interested in looking at aging mechanisms in an unbiased way, whether through genetic interventions, or pharmacological interventions, we're not beholden to a particular mechanism, per se."

"Having been involved in the basic biology of aging and trying to understand the degenerative changes of aging from a mechanistic perspective for many years, that resonated with us. And so we put together a proposal focused around some of the ideas, particularly with regard to an unbiased way to identify molecules which might retard the aging process. We pitched it to Y Combinator, they really liked us and gave us a million dollars to start the company. It was certainly the fastest million we ever made in our careers!"

"You often hear people say they 'target aging' but you have to ask what does that mean - does it mean targeting a pillar of aging: senescence, inflammation, mitochondrial dysfunction? That's not targeting aging - that's targeting something other people have said is linked to aging processes. Everyone is very familiar now with using those terms, but it roots you in the idea that we understand what aging is, and we don't think we do. We believe that these pillars of aging are just one of many, and we think that the major modulators of aging remain to be discovered."

Gerostate Alpha: "Our phenotype is lifespan"

At the platform's "front end", the high throughput screen is predominantly based on lifespan extension data from a variety of strains and species of Caenorhabditis nematodes - simple, short-lived organisms, which allow manipulations of lifespan to be studied more easily. "At the back end, we phenotype the successful interventions that target different aspects of aging, in mice. And we're looking at multiple indications simultaneously, whether muscle dysfunction, lung function, bone function, cardiac function, the central nervous system to some extent. All of these things are screened for simultaneously. And I would argue this is something we can do better than anyone else."

The founders' confidence is largely because of the infrastructure that has been built up at the Buck Institute over many decades, and which would cost tens of millions of dollars if a start-up were to attempt to replicate it. "Our initial strategy was to screen small molecule libraries, so we did that on around 60,000 compounds, and we identified over 30 hits that have been validated. We're now prepping those and derivatives of those into lead candidates to move into our preclinical mouse models. But in parallel to that, we screened some libraries of off-patent compounds, and we've moved those through into preclinical mouse models already. We've had some really interesting hits and we're now doing our follow up experiments on the pathways involved in those and the efficacy of those compounds, in those specific tissues."

Comments

It is said that fixing the damage takes to age 122 max and then it's DNA. I wonder... if urine has 4000 chemicals and there are over 100,000 chemical reactions in each cell, identifying all the damage reactions is going to take a considerable effort let alone interventions.

Posted by: tony at January 27th, 2021 4:13 PM

Screening small molecules in the hope to make marginal result is a false way, waste of time and money.

Posted by: Ariel at January 27th, 2021 4:45 PM

@Ariel - I think saying "all small molecule" approaches are a waste of time and money is a bit of a blanket statement.

For example Underdog are using a cyclodextran to try and remove oxidised cholesterol from macrophage foam cells in the atery walls, technically that is a small molecule approach to damage repair. Although it wasn't discovered via a large scale small molecule screen, but came instead from (biased) rational design.

Why are small molecule screens ineffective in finding small molecules that can remove damage from the body? Because they often have side effects? Or because the search space is to large and molecule libraires are to small for an unbiased approach to have a chance of turning up something useful?

Posted by: jimofoz at January 27th, 2021 6:11 PM

@tony
First, we know that 122 is the current human lifespan record. All without fixing the damage, just being lucky AND having good, albeit not exceptionally so, genes.

On e other hand, If you can fix any damage then there's no reason to believe there's a hard lifespan limit.

The damage here means not only wounds but also wear and tear, accompanied by disregulation of all the body pathways.

What you are implying is what Aubrey calls messing with the metabolism to slow the damage accumulation by various means. There are some repair mechanisms which can be boosted like autophagy, special supplements like NAD+. There might be small chemicals to improve cell DNA repair , which are close to p16 cellular pathways.

While impressive those approaches will only slowdown or make more palatable the aging process. A comprehensive repair can literally turn back the clock. And in some cases might be easier to revert to the healthy state than trying to prevent myriad of possible ways the body gets damaged.

For example, if you can culture stems cells and replace all the tissues and organs, you don't have to know how exactly they go bad. Just apply the fix...

Of course getting there is an immensely difficult task. It will take for sure many decades. However, the intermediate points and bridge treatments while only partial can be very interesting in the short term.

like life and death difference for many of us, yet insignificant on the grand scheme of things...

Posted by: Cuberat at January 27th, 2021 11:47 PM

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