Investing in Anti-Aging and Longevity
Imagine breakthrough, anti-aging therapeutics are successful. Everyone alive will live to 150 years old. Which new businesses should be built?
I’ve outlined thoughts on why Longevity is interesting and where a venture investor might look to place a bet —
Aging is characterized by a progressive loss of physiological integrity, leading to impaired function and increased vulnerability to death. Longevity science (an extension of gerontology) is focused on a foundation layer of biological and cellular health believed to underpin many branches of age-related deterioration. This deterioration could potentially be the primary risk factor contributing to major human pathologies, including cancer, diabetes, cardiovascular disorders, and neurodegenerative diseases.
Aging research has experienced an unprecedented interest over recent years, particularly with the discovery that the rate of aging can be slowed through management of genetic pathways and the biochemical processes conserved in evolution. The potential for therapeutic success has heightened due to advances in genomic sequencing, machine learning, and genomic computation.
Today, there are a diverse range of regenerative medical therapies for the repair of all age-related damage to human tissue with the ultimate purpose of maintaining a state of negligible senescence (biological aging) in the patient, thereby postponing age-associated disease.
It’s important to get a sense for the theorists of the 19th Century and the subsequent scientific milestones that have allowed for this type of approach to be possible. Below are a few noteworthy scientific contributions.
- August Weismann  Programmed Death Theory: Proposes that programmed death assists the evolution process by removing older animals from the population and thus freeing resources for younger, more evolved, animals.
- Peter Medawar  Mutation accumulation theory: Suggests aging is an inevitable result of the declining force of natural selection over time.
- Denham Harman  Free Radical Theory of Aging: States that organisms age over time due to the accumulation of damage from free radicals in the body.
- Leonard Hayflick  Hayflick Limit: Demonstrated that a normal human fetal cell population will divide between 40 and 60 times in cell culture before entering a senescence phase.
- Lloyd Smith and Lee Hood  Creation of the world’s first fluorescence-based automated DNA sequencing instrument at CalTech.
- The Human Genome Project  was an international scientific research project with the goal of mapping the entire sequence of nucleotide base pairs that make up human DNA.
- Jennifer Doudna  discovered CRISPR Cas9 genome, reducing the time and work needed to edit genomic DNA.
Often-cited, “The Hallmarks of Aging” paper was published in 2013 by Carlos Lopez-Otin and enumerates nine tentative hallmarks that represent common denominators of aging in different organisms, with a particular emphasis on mammalian aging. These foundational cellular and biological problems include genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication.
Based on similar underlying research, bio-gerontologist Aubrey de Grey and the SENS Research Foundation have also pioneered a slightly different framework for understanding and reversing the damages caused by aging. The organization has established seven systemic issues and corresponding strategies to tackle the cellular hallmarks of aging. Including, nuclear mutations, mitochondrial mutations, intracellular junk, extracellular junk, cell loss and atrophy, cell senescence, and extracellular crosslinks.
Many agree that the solution to longevity may come from one or several approaches. These approaches include tissue rejuvenation, caloric restriction, stem cells, molecular repair, gene therapy, pharmaceuticals, and/or direct organ replacement.
Examples of Treatments
Cataracts typically form in old age due to protein cross-linking catalyzed by sugar intake. SENS is considering developing enzymes that react with and unbundle hardened tissue to reverse and prevent cataracts.
Intermittent fasting and ketogenic diet have proven to extend life spans in mice. Dr. Satchidananda Panda of the SALK Institute found that an 8-hour time restricted feeding produces weight loss in obese humans, though effect on longevity is unclear.
In 2017 Harvard Stem Cell Institute published an early success in attempting to replace damaged sound-sensing hair cells using highly regenerative stem cells from intestinal stomach lining.
Cells recycle old proteins and other molecules into vesicle called a lysosome. Lysosomes contain many proteins and destroy the engulfed cell pieces. Genes for these proteins sometimes mutate, causing Parkinson’s disease. Improving the cleansing agents at the molecular level may prevent some neurodegenerative diseases.
In 2016, telomerase gene therapy was used in a mouse model of aplastic anemia and provided increased and stable telomerase expression. Using this type of therapy to delete the genes for telomerase shortening and to eliminate telomerase-independent mechanisms from turning normal cells into cancerous cells could progress longevity.
This approach uses a combination of cells and bioengineered materials to improve or replace biological tissues. In April 2006, Professor Anthony Atala M.D. at Wake Forest University reported a successful trial of seven bladders grown in-vitro and given to humans.
Due to its potentially foundational relationship with pathological diseases experienced in old age, the size of the longevity market is theoretically larger than that of elderly spending on cancer, dementia, and diabetes combined (not including arthritis, kidney disease, cataracts, hearing, etc).
For easy math, we might assume that all healthcare spends by population aged 65+ was all technically longevity-related spend. This would mean a minimum market size of $800B assuming no spend on longevity in populations earlier than 65 years old.
But that’s not enough. Longevity science, if successful, would jumpstart a number of adjacent opportunities along the healthcare value chain. This might mean advanced wet-lab machinery, new anti-aging facilities, alternative distribution channels, new computational cost, deeper data storage requirements, and more.
While any exact estimate would be incorrect, it’s fair to say the longevity market is in the trillions. Not just because of the size of elder spending on healthcare today, but because in order to sustain a longer life, elders would likely need to keep spending, allocating dollars to longevity in perpetuity.
Before we begin to evaluate individual competitors in the longevity space, it’s important to recognize that our current definition of longevity has constrained this discussion to a small segment of the healthcare value chain. Opening up the discussion to care providers and financial intermediaries introduce a number of additional opportunities.
These buckets are not discrete, but provide a framework by which to evaluate existing players. Below I’ve also listed a few noteworthy events in the longevity sector that point to meaningful activity across active incumbents, growth stage ventures, an early stage ventures.
Thus far, we focused on the production stack because it is the originating function of innovation in the context of longevity. Breakthroughs at this point in the value chain will generate a bullwhip effect of new economic activity in adjacent segments.
- Recently completed $300m investment in 23andMe as well as announced 4-year exclusive partnership to identify novel drug targets.
- $4.3B acquisition of Spark Therapeutics, a pharmaceutical company developing gene therapies with 6 drugs in late stage pipeline.
- The company focuses on the mechanistic target of rapamycin (mTOR) pathway which regulates aging. IPO’d on Nasdaq in January 2018 at $400m market cap.
- Machine learning-based drug discovery platform created to accelerate the discovery of therapies for aging. Completed financing of $18m Seed led by General Catalyst and First Round.
- Biopharmaceutical platform intended to discover novel protein-based therapeutics. Completed Seed financing of $4.3m Seed led by Felicis Ventures.
Exploring Investment in Longevity
4 approaches (not discrete)
- Portfolio approach to longevity
- Picks and shovels
- Own the customer channels
- Secondary business models (if longevity works, then what?)
Portfolio approach to longevity
Ability to invest in one individual biological or cellular approach to longevity requires a deep specialist knowledge and high degree of conviction in a therapeutic strategy. Instead, a risk-hedging investor might take a portfolio approach, placing bets laterally across promising early stage teams, using founder-market-fit and co-investors as strong heuristics.
If an investor were to place an individual bet directly in the therapeutics space, then only a computationally advantaged therapeutics firm would make sense. This would mean investing in a competitor to Recursion Pharmaceuticals, Spring Discovery, Juvena Therapeutics, etc.
Request for Startups
Picks and Shovels (enabling services)
The size and complexity of genomic datasets are ever-expanding, requiring biologists to apply increasingly sophisticated computational tools for analysis, interpretation and storage of this information. The genetic problem of longevity is increasingly becoming a computational rather than biological problem.
Investing in the computational layer instead of point solution therapies de-risks the exposure common to traditional pharma (as mentioned, would require a diverse portfolio). Computational tools have an opportunity to generate value near-term, whereas therapeutic solutions require 5–10 year experimental phases before producing any cash.
Noteworthy company: Serotiny
- Building a platform that “democratizes synthetic biology”, putting a sophisticated discovery platform, designed to iterate novel proteins constructs, directly in the hands of researchers. Raised a $3m Seed from 8VC and NanoDimension in July 2018.
Lowering Barriers for Clinical Trials
The clinical trial market has seen significant growth in the past decade, expected to reach $65B by 2025. Lowering the barriers for clinical trials will significantly reduce the time-to-market for gerontological drugs. We’ve seen advances in the space from larger companies already. Apple’s ResearchKit open source framework was introduced in 2015 and enables developers to create powerful apps for medical research. Elligo’s ‘Goes Direct’ program makes it easy for physician practices to become clinical research sites and to extend new treatments to patients.
Noteworthy company: Trials AI
- Trials AI harnesses data from codified clinical trials databases to offer insights across therapeutic areas to trial sponsors, thereby enabling users to unlock information and make recommendations to trial sponsors. In early 2018, the company raised $75k in pre-seed funding from Dreamit Ventures.
Creative Financing Schemes
Only 2–3% of homeowners have considered reverse mortgaging, though this may become more popular as healthcare costs rise and the aging population looks to liquidate assets to cover. Life insurance settlement markets are also relatively under-advocated. Less than 3% of life insurance plans are settled each year, while 2 million Americans annually lapse coverage, losing access to life insurance payouts.
Own the Customer Channels
23andMe, Viome, Helix, uBiome and others have used a DTC approach to create relationships with consumers on the vector of ‘quantifying self’. On the backend, these relationships have become marketing channels that traditional therapeutics providers — like GlaxoSmithKline — are willing to pay for significantly. Perhaps further opportunities exist to create better positive feedback loops inside customer networks. This strategy might play on an individual’s desire to use genetic data to connect with others via maps of genetic proximity involving extended family and friends.
Eldercare as a Channel
There may be opportunities to creatively and safely use Care.com and Honor caretakers as channels into patients. Additionally, eldercare facilities might act as channel partners for clinical trials or host safe, on-site longevity care services.
Lifestyle as a Wedge
Apple Watch users can share fitness routines with family, friends, and trainers to remain accountable. This does a good job of incenting competition-driven network effects. Now, with significant wrist real estate, Apple can embed higher quality technologies (like the ECGs) to provide better health data (virtuous cycle) and own deeper patient lifestyle datasets. Fitness apps like Strava, MyFitnessPal, and others play on the same strategic vector.
Secondary Business Models
Advantaged Insurance Models
Life insurance companies have the obvious opportunity to increase the number of premium payments before paying a death claim. In addition, lesser-known longevity insurers collect premium dollars from policyholders to eventually pay income when a policyholder lives a long life, instead of paying a death claim as in ordinary life insurance.
If longevity sciences reach successful conclusions in the next several years, humans will still need to solve for the time constraints placed on female reproductive organs. Increasing longevity against the same pace of reproduction might be harmful when considering resource constraints. Today, IVF is the most common solution, though only 37% of assisted reproduction cycles for women under 35 result in live births. Companies like Modern Fertility are taking the informational DTC approach, creating high-quality customer experiences while still using traditional CLIA-certified labs like Quest.