The Reason behind Longevity: start-up opportunities

We connected with Reason (the person) to get the inside track on hot areas for Longevity R&D.  

Longevity.Technology: Advocacy runs through Reason like a stick of rock; committed to showing the world that aging isn’t inevitable, he is both co-founder and CEO of Repair Biotechnologies, “a longevity company with the mission to develop and bring to the clinic therapies that significantly improve human healthspan through targeting the causes of age-related diseases and aging itself,” and the man behind Fight Aging!, a popular Longevity advocacy blog.

A key focus for Reason is helping important Longevity research get out of the lab and into the wider world – that needs seed money. We spoke to him about the key areas of Longevity research and development for biotech startups.

1. A viable approach to medical tourism for the era of rejuvenation therapies
Reason: “The medical tourism industry is unhelpful. Radical change and improvement is needed to allow rejuvenation therapies to be allowed to expand to their full potential. This is a great opportunity for any company to successfully smooth the road of regulatory arbitrage, allowing people in restrictive regulatory regions to effectively make use of reputable services available in other countries.”

Note: We covered the world’s first IRB-approved clinical trial for tourists to Colombia, the $1m price tag trial is aimed at reversing aging by at least 20 years.

2. Restoration of hematopoietic stem cell function
Reason: “Responsible for producing blood and immune cells, as well as maintaining blood vessel integrity, hematopoietic stem cells are crucial. They degrade with age and the immune system plays such a vital role in aging that a solution must be found. The existing standard approach to bone marrow transplantation (chemotherapy) is too harsh to a preventative therapy, but potential alternatives, such as mobilising stem cells to leave the bone marrow, are showing promise in the lab, but we need to progress them.”

3. A low-impact method of destroying the peripheral immune system
Reason: “Keeping an immune system at peak function means clearing it of the senescent and dysfunctional cells that gather with age. Destroying dysfunctional cells can be beneficial, but it needs to be done without undue side-effects. Something akin to suicide gene therapies or other targeted means of low-impact cell destruction is needed, and efforts should be focused in this area.”

4. Build a physician network to bring low-cost senolytics to the masses
Reason: “There is already compelling evidence that dasatinib and quercetin clear senescent cells, with results on how well fisetin performs in humans expected soon. Although these substances cost little, an efficient, widespread delivery network is lacking. Functional senolytics have the capacity to greatly improve the state of health for every older person, so their existence should be promulgated, the distribution widened and the right to off-label use of approved drugs exercised.”

5. A competitor for Revel Pharmaceuticals in glucosepane cross-link breaking
Reason: “Persistent cross-links between extracellular matrix proteins stiffen blood vessels and cause fatal hypertension. The market size for methods of reversing this outcome of aging is huge, and breaking cross-links is a plausible way forward given what is known of their biochemistry, but Revel Pharmaceuticals is presently the only startup biotech company working on this, developing ways to break down the primary form of persistent cross-link in human tissues based on glucosepane. There is room for more, especially as this part of the field is presently at the same point that senolytics were five to ten years ago, and most likely has a similar trajectory ahead of it.”

6. Interfere with telomere lengthening to defeat all cancers
Reason: “The requirement for telomere lengthening is the Achilles’ heel of cancer, so cancer cells abuse either telomerase or alternative lengthening of telomeres (ALT) to lengthen their telomeres and continue unfettered replication. Successfully sabotage this process and any cancer will wither as a result, no matter how advanced it is. This is truly the best basis for the development of a single, universal cancer therapy, and numerous potential approaches exist at various stages of development. Some have made it to the point of preclinical work (Maia Biotechnology), but most have yet to make the leap from academia to industry. There is considerable opportunity here to revolutionise the cancer treatment.”

7. Break the link between DNA repair and epigenetic change
Reason: “DNA double strand break repair causes epigenetic changes that are characteristic of aging. Understanding the intricate and complex DNA repair mechanism of the cell nucleus might allow us to intervene and slow or halt this process of epigenetic change. This part of our biochemistry is comparatively well mapped, DNA repair well-researched, so the starting points for therapies are in there – we just need to find and exploit them.”

8. Restore lost mitochondrial function to a much greater degree than can be achieved via NAD+ upregulation
Reason: “NAD+ is headline stuff at the moment, but although it restores the quality control mechanism of mitophagy in old cells to restore some mitochondrial function in older subjects, the effect is similary to that of exercise, judging from the few, small, human trials conducted so far. If mitochondrial function could be fully restored, the benefits could be sizable, so different approaches (epigenetic reprogramming in vivo, delivery of whole mitochondria to tissues, targeted destruction of damaged mitochondrial DNA, alter gene expression to remove mitophagy impairment) should be investigated. Any group able to demonstrate significantly better outcomes in animal models than have been obtained from NAD+ upregulation should have no issues in raising funds for commercial development.”

9. Restore a youthful human gut microbiome
Reason: “The human gut microbiome changes as we age. The levels of specific metabolites decrease and the change in the balance of beneficial and harmful gut microbes leads to greater chronic inflammation. In animal studies have shown success in microbiome transplantation and faecal microbiota transplantation is well developed for use in a number of pathological conditions in humans. The next step is to apply this to aging, providing microbes directly and developing probiotic-like treatments. Given the diverse influences of the gut microbiome and the metabolites it produces, this may be a way to meaningfully reduce chronic inflammation, restore stem cell activity, and generally improve health in older people.”

10. Reverse the loss of capillary density with age
Reason: “Capillary density declines throughout the body with age, reducing delivery of oxygen and nutrients to cells and tissues, particularly in the brain and muscles. Although this mechanism is not very well understood, the processes of angiogenesis in general, the regulatory mechanisms governing generation of blood vessels, are fairly well explored.

There is an opportunity here to take what is known and apply it to capillary density loss reversal, preventing the loss in tissue function that occurs with age. Loss of capillary density is directly implicated in neurodegeneration and heart failure, providing well-understood indications to target for any company working towards this form of repair biotechnology.”