Fight Aging!

As I noted recently, it is somewhat surprising to see so little movement towards the clinic in the field of autophagy enhancement over these past two decades. It has been an area of strong interest in the research community for at least that long. It is well known that upregulation of the cellular maintenance process of autophagy is an important part of the calorie restriction response, a sweeping change to metabolism that slows aging and improves health. Sizable investment in the development of calorie restriction mimetic drugs has taken place in the past fifteen years. Why then has the research and development community failed to do all that much with the direct upregulation of autophagy, despite a steady flow of papers and interest? I don't have the answer to that question, but I'll note that it isn't an unusual situation. There are many areas of research relating to aging in which all that is lacking, it seems, is the will and funding to make the leap to commercial development.

Given that, we are now at the point at which the first rejuvenation therapies worthy of the name, senolytic treatments that can clear senescent cells, has energized the investment community. Suddenly quite large amounts of funding are available for any line of work that might slow aging. The people managing venture funds, who are on a countdown of just a few years when it comes to finding placements for funding, are now sifting through the entirety of the scientific output related to aging from the past three decades, looking for possibilities. Autophagy upregulation is an obvious one, even if only on the basis of the sheer volume of research on this topic, and so companies focused on autophagy are now being founded and funded.

Taking a brief and partial glance at what is out there, Life Biosciences has Selphagy Therapeutics as a portfolio company, and as noted here Apollo Ventures has funded Samsara Therapeutics. I suspect this may be more to do with seeking a platform for small molecule drug discovery that autophagy specifically; if you look at Juvenescence and possibly other funds, the first point of entry into this field has been to invest in companies that will provide a drug discovery pipeline, not just a focus on one target.

Do I think that autophagy upregulation is a good use of resources? Well, yes, autophagy declines with age and it is widely agreed that this is a bad thing. But it is a matter of luck and happenstance at this stage when it comes to finding compounds that might produce greater upregulation than is achieved by the practice of calorie restriction. Even then, we know that calorie restriction does good things for health but little for life expectancy in humans. When the treatment exists and is free, then yes, go for it. But if we are to pour countless millions and entire careers into developing novel therapies for aging, why build things that can at best only shift more people into the higher end of natural variations in human longevity? That is aiming low, and we don't have to aim low. Those of you reading the articles below and thinking "where can I get this compound" should instead be asking "what is the size of this effect?" and probably choosing to eat less instead.

Samsara Therapeutics Closes Seed Round Led by Apollo Ventures

Samsara Therapeutics, Inc. ("Samsara,") a platform biotechnology startup engaged in the discovery and development of compounds that address the primary molecular causes of aging, announced today the closing of a seed financing round. The financing was led by Apollo Ventures, a life sciences venture capital firm and company builder working across Europe and North America. Additionally Nature Communications published a peer-reviewed paper, "The flavonoid 4,4′-dimethoxychalcone promotes autophagy-dependent longevity across species" authored by Samsara's scientific team. The paper demonstrates the capability of the Samsara platform to identify novel geroprotective small molecules that extend healthy lifespan across species and which are protective in mammalian models of disease.

The particular molecule (4,4'-dimethoxychalcone) is a natural product derived from the Japanese longevity herb known as Ashitaba. Samsara Therapeutics is conducting medicinal chemistry optimization of this compound and other Samsara platform-identified compounds in collaboration with Evotec. "This paper moves us closer to our goal of conducting the largest-ever exploration of the chemical space around natural products that extend healthy lifespan. Virtually all of the known geroprotectors have been natural products or derived thereof, and were identified via phenotypic screening. The time is ripe for this comprehensive approach due to methodological advances in phenotypic screening, target ID, and molecular mechanism of action analysis."

The flavonoid 4,4′-dimethoxychalcone promotes autophagy-dependent longevity across species

Ageing constitutes the most important risk factor for all major chronic ailments, including malignant, cardiovascular and neurodegenerative diseases. However, behavioural and pharmacological interventions with feasible potential to promote health upon ageing remain rare. Here we report the identification of the flavonoid 4,4′-dimethoxychalcone (DMC) as a natural compound with anti-ageing properties. External DMC administration extends the lifespan of yeast, worms and flies, decelerates senescence of human cell cultures, and protects mice from prolonged myocardial ischaemia. Concomitantly, DMC induces autophagy, which is essential for its cytoprotective effects from yeast to mice.

This pro-autophagic response induces a conserved systemic change in metabolism, operates independently of TORC1 signalling and depends on specific GATA transcription factors. Notably, we identify DMC in the plant Angelica keiskei koidzumi, to which longevity- and health-promoting effects are ascribed in Asian traditional medicine. In summary, we have identified and mechanistically characterised the conserved longevity-promoting effects of a natural anti-ageing drug.