Sebastian Aguiar – Aging Research and Investment

Today, we have an interview with Longevity Investor Network member Sebastian Aguiar, who has kindly shared some of his thoughts and motivations with us. Sebastian Aguiar is a Venture Fellow at Apollo Ventures, an aging-focused venture capital fund and company builder that invests across Europe and the United States. He can be found on Linkedin and Twitter.

What initially attracted you to aging as a general discipline?

Aging is already a solved problem… for cells. The germline is immortal. Cancer cells are immortal as well. In fact, cellular immortality has been a solved problem for 3.5 billion years, since the dawn of life on Earth. It’s just that the soma – all the cells other than the reproductive cells – are disposable.

This principle is one of the key evolutionary biology theories of aging: the ‘disposable soma’ theory. The theory also explains why caloric restriction and fasting extend lifespan – when there is not enough food around, or a famine, the body will wisely not invest in reproduction because the available resources cannot sustain more people or ‘mouths to feed.’ In response, the body ‘hunkers down’ or invests in self-repair in order to outlast the famine and reproduce when food again becomes plentiful. The disposable soma theory, coupled with the theory of antagonistic pleiotropy, have enormous explanatory power.

Another watershed event: Shinya Yamanaka and John Gurdon shared a Nobel Prize for iPSCs and somatic cell nuclear transfer – demonstrating the possibility of violating the ‘Weismann Barrier’ described by the eminent developmental biologist August Weismann – that genetic information can be transmitted from soma to the germline. In that process, aging markers such as the Horvath methylation clock are erased.

Through multiple, orthogonal, potentially synergistic interventions, we are able to extend the healthy lifespan of model organisms. In mice, the ablation of senescent cells can extend median lifespan by 30%. The augmentation of autophagy and the transient re-activation of telomerase yield similar rejuvenating effects. These interventions should be combined, as they may be synergistic. It is only a matter of time before these interventions are working in the clinic.

This kind of evidence was enough for me to commit my career to geroscience because, many years ago, I saw that the ‘writing is on the wall’ – thanks to advances in molecular biology, healthy life extension is no longer science fiction. This century, geroscience will be a paradigm shift comparable to the antibiotics revolution in the last century.

The books that first piqued my interest in aging were Aubrey de Grey’s “Ending Aging” and Michael West’s “The Immortal Cell.” Honorable mention goes to Lenny Guarente’s memoir “Ageless Quest.” The seminal article “The Hallmarks of Aging” is a great primer on the biology itself.

What is the main challenge you have faced as a longevity investor?

Most geroscientists are not working on translational research. They are basic scientists. Basic science is the bedrock of everything we do, but it’s not enough. Pharma has dropped the ball in drug discovery and development, and there is a major gap in the pipeline between academic proof-of-concept and drug development. There is not enough collaboration between biologists, chemists, and drug hunters. The transition through the ‘valley of death’ of drug development is where company-building venture capital firms such as Apollo Ventures can step in.

For example, there are many biologists with data showing that gene X or protein Y, when modulated, has salutary effects. They might even identify a ‘hit’ molecule, such as a natural product or library compound that modulates the target or mechanism of action, but they usually don’t partner with chemists to perform medicinal chemistry optimization, pharm/tox, and validation in multiple animal models of disease.

The other challenge is that, as investors, we don’t see many established, aging-focused biotechs that satisfy our investment criteria. The science may be solid, but the team is lacking, or vice versa. There are not many experienced C-level biotech managers out there, and few understand geroscience. This will change once the field has a few clinical successes. Then the floodgates will open.

Another big problem: The NIA has a budget of $3B USD. Half goes to Alzheimer’s research, a large chunk of which is spent on the failed amyloid hypothesis. Another portion of the NIA budget goes to social science studies, such as such pressing questions as “What kind of language should we use to refer to old/elderly/aged people?” i.e., semantics and low-impact, opinion-based hot air. Only a few percent of the NIA budget actually goes to the hardcore research – the fundamental biology of aging and therapeutics addressing the Hallmarks of Aging. Government funding is the fount of innovation, and the entire industry relies upon the NIA making wise choices in awarding grants.

How have you seen the longevity startup ecosystem mature over the last few years?

It’s still very early days. There are now a handful of other VCs and angel investors focusing exclusively on the space. The emergence of Calico was a galvanizing event, as was Unity Biotech. Jim Mellon has done his part by proselytizing in the UK ecosystem. Singapore has been receptive, and Brian Kennedy is doing his part there. Unity’s clinical trials and the TAME metformin trial of Nir Barzilai are on the horizon. This pace will only continue with each little win, and more will enter the fray. It’s a positive feedback loop.

What do you think is lacking in the longevity investment ecosystem?

Capital and great teams. They will come with time. The science is already solid. The bottleneck is company formation.

How do you personally evaluate longevity companies?

This is a long discussion. Here is a graphic to summarize my approach:

We like to see lifespan extension as well as the amelioration of one or more animal models of disease (age-related or not). Since aging is not widely considered a disease for which a physician can prescribe a medicine, we need to pursue particular clinical indications as any other VC would. The difference is that our therapies aim to become ‘a pipeline in a pill’ – meaning that one drug can be prescribed for a multitude of diseases and, ultimately, the aging process itself. That requires us to have a very high threshold for safety.

Here is a ‘Preclinical Asset Evaluation Matrix’, or PAEM framework, that I use for evaluating projects. The details are part of the Apollo secret sauce, but this will provide a taste.

What is Apollo Ventures’ approach to longevity investing?

We build companies in close collaboration with geroscientists. We constantly scan the literature. We attend most of the aging conferences and meet with as many geroscientists as possible.

Apollo can also invest in established companies, but we are very selective. We would rather build the company and team from the ground up and tailor them to our criteria.

We see a great opportunity in acting as a bridge between excellent European science and the US marketplace. We invest in both the US and Europe but hope to expand to Asia in the coming years.

What can we expect from you and Apollo Ventures in 2019?

We will unveil a few more geroscience companies that are currently in stealth mode. Apollo will continue to build our internal team as well. We are looking for people with talent in both geroscience and biotech business management. Apollo was founded by a partnership of successful entrepreneurs and aging scientists with expertise in the biopharma and management consulting businesses. The depth of scientific expertise and biopharma business acumen within Apollo is unique in the geroscience space. Another distinguishing feature is that Apollo is focused more heavily on company building than other investors who are oriented toward investing in pre-established companies.

Can you tell us a bit about the portfolio companies that you are most excited about?

Aeonian Pharmaceuticals – the best-in-class rapalogs, highly selective for mTORC1 over mTORC2. Stay tuned for publications and news flow.

Cleara Biotech – developing senolytics targeting the FOXO4-p53 protein-protein interface. This is the original FOXO4 company. Cleara is also building a broader pipeline around cellular senescence.

Samsara Therapeutics – the largest pipeline for geroprotector screening and drug discovery in the world. This is an engine to discover the next rapamycin or metformin-type geroprotective small molecules based on the pillars of natural products chemistry and phenotypic screening. The primary focus of Samsara is proteostasis enhancement. Samsara will come out of stealth mode soon.

We have several more in stealth mode. In all of our companies, we have partnered with the leading founding scientists in their respective fields.

What has your experience been as a member of the Longevity Investor Network?

Quite positive; I’ve been privy to interesting pitches and discussions. The Longevity Investor Network will be a critical nexus of collaboration as the longevity and geroscience space evolves and expands.

Why did you decide to join the network in the first place?

Deal flow and to meet fellow investors.

What have you found most valuable from the network?

Same as above.

Any specific longevity areas we should keep an eye out for in 2019?

Parabiosis and reprogramming are both ‘new kids on the block’. Also, insights from supercentenarian genomes will yield new targets and mechanisms for intervention. The rejuvenation of cells ex vivo for cell therapy is also relatively close to the clinic. Enhancing proteostasis or mitochondrial function (biogenesis and mitophagy) are also compelling areas. A very interesting paper from Cynthia Kenyon’s lab showed that a proteostasis process similar to microautophagy is implicated in germ-line rejuvenation in C. elegans. The mechanisms that confer germline immortality are really the Holy Grail of geroscience; they will light the way. Evolution has already figured out how to keep cells young.

One underappreciated area is ‘jumping genes’ — transposons or transposable elements, such as LINEs. These parasitic DNA elements become unleashed with age, as they are normally repressed by KRAB zinc finger nucleases and sirtuins such as SIRT6. They induce genomic instability, senescence, and inflammation. It would be interesting to see more mechanistic work establishing the causality of transposons in aging – i.e., does silencing transposons extend healthy lifespan?