Who wants to live forever?

Aging, longevity and the longevity market

Aging

For hundred of years, philosophers and scientists have tried to wrap their heads around the manifold wonders of aging. Aristotle — the originator of the scientific study of life — had also a theory of aging. For him aging was a process that all living things undergo, life was essentially tied up with soul while his four general « rules of longevity » were:

1. The longest-lived plants enjoy greater longevity than the longest-lived animals.
2. Blooded animals live longer than bloodless.
3. Terrestrial animals live longer than aquatic.
4. Large animals live longer than small.

He believed all animal bodies consist of the “hot” and the “cold”, the “dry” and the “wet”. An animal is by nature “hot and wet”, and in some sense this is what it is to be alive (warm and moist). But old age is “dry and cold”. On this picture, the process of aging is tied to the gradual drying up of the internal moisture necessary for life. And he was convinced that two of the primary factors that might prolong this drying up were: the quantity and the quality of moisture. And that more or less was his theory: Aristotle’s Theory of Aging.

Even though it was the 20th century that has seen the rise of multiple aging theories and even though only now we have the means to inspect and manipulate biological systems with precision unavailable to our predecessors, we still don’t have a clear understanding of what the ultimate cause of aging is.

We know for example that aging — the process of becoming older — involves a series of functional changes that appear over time and are not the result of illness or accident but occur as the result of accumulating disorders (the nine hallmarks of aging) in the body’s structure and functions that will give rise eventually to different aging dependent pathologies. In this context, we view aging as an unpreventable chronological, social and biological process that is genetically determined and environmentally modulated.

Moreover, we accept aging as a gradual, multifactorial, time-dependent process that progressively affects most regulatory mechanisms due to the hierarchical organization of living systems. Therefore, dysfunctions affecting only a few biological processes within the cells of one or several organs can propagate to all parts of the body. This explains why aging cannot be fully understood or controlled when monitoring only a restricted number of physiological processes.

But how we determine aging? When aging starts? How we obtain longevity? Well, the answer to all these is still less than obvious. However, one thing is for sure “if you take care of things, they last (more)” and this can be true also for humans.

Aging or Longevity

The ability to define aging (the nine hallmarks of aging) and longevity (life span) separately has become possible only in recent years. Biogerontological research conducted during the last two decades has, to a large degree, solved the evolutionary problem of longevity and aging. Evolutionary theorists have mathematically and empirically demonstrated that longevity is genetically determined from genes that are selected for a reproductive advantage, and not by genes that were expressed only late in life. So, longevity evolved and was directly related to genes that optimized survival to the age of reproduction (Aging and Longevity: Why Knowing the Difference Is Important to Nutrition Research).

On the other hand, aging is not a product of selective evolution. The aging process more closely reflects chance events that affect biological systems during development or during the early reproductively-active years. So, aging will be best understood by evaluating biological systems during development that are most susceptible to time- or event-dependent alterations leading to functional loss and chronic conditions in old age.

Longevity in the animal kingdom starts with biological immortality (organisms do not age), a state in which the rate of mortality from senescence is stable or decreasing, thus decoupling it from chronological age, and it is claimed that various unicellular and multicellular species (including some vertebrates) have achieved this state (bacteria, yeast, hydra, jellyfish, lobsters and planarian flatworms).

As to modern humans the closest we have to biological immortality or eternal youth are the communities of the centenerians that can be found around the world in the so called Blue Zones. The Blue Zones (Okinawa, Japan; Sardinia, Italy; Nicola, Costa Rica; Icaria, Greece and Loma Linda, California) are regions of the world where these “naturally induced” centenarians live healthier and longer lives than others. The lifestyle of these blue zones people orbits around: Moderate, regular physical activity, Life purpose, Stress reduction, Moderate caloric intake, Plant-based diet, Moderate alcohol intake, especially wine, Engagement in spirituality or religion, Engagement in family life and Engagement in social life.

But when it comes to “technically induced” centenarians, well, some of the craziest attempts by humans, to reach immortality or eternal youth, have been so far the following:

1. Inject themselves with extracts from the testicles of guinea pigs and dogs,
2. Mummify themselves to death in the hope of achieving immortality,
3. Cryogenically frozen themselves (after death), hoping one day that they will be properly unfreezed and revitalized,
4. Drink a potion made with menstrual blood (menstrual blood-derived stem cells, MenSCs) or infuse themselves with the blood of young people. Keep in mind that the Count Dracula Approach was firmly denounced by the FDA, as a result the startup Ambrosia — offering $8000 “shots” of fresh blood — was closed down (after all people can die from poop transplant not to mention infected blood),
5. Or embalm and preserve their brain and upload their “consciousness” into an android (digital brain) — whatever consciousness means of course — while choosing for a body among a collection of robots.

Of course Chinese alchemists went one step further, they spent centuries formulating elixirs of life with toxic mercury, gold, sulfur and plants, and as a matter of fact the formula for gunpowder was originally an attempted elixir of immortality…

So, yes immortality and eternal youth have tormented humanity since the first H. sapiens witnessed death and realized his or her own eventual demise. Consequently the obvious answer to Freddie Mercury’s question “Who wants to live forever?” is definitely “A lot of people would like to live longer or for ever”.

As a result, it is not a surprise that the Bank of America believes innovation in “ammortality” products in the wellness space, could soon prolong healthy human life well beyond 100 years. These “ammortality” theme, is actually expected to be worth $504 billion by 2025, by helping to improve health spans and lifespans to the betterment of human vitality, enabling the world population to live freer of disease rather than forever.

Moreover, with the global spending power of people aged 60 and over anticipated to reach $15 trillion in 2020, the rise of a new continent —  the 7th Continent —  with 1 billion people in retirement globally is actually a fact.

To cut a long story short, the entire Longevity industry — the study of aging with the ultimate aim of delaying its diverse diseases and its financial industry — will play a predominant role in the future (when coupled with scientific pragmatism and AI) and is estimated to worth $ 27 trillion by 2026.

Longevity Industry and Startups

The longevity industry — once considered an expensive eccentricity of the ultra rich — has grown in the past 4 years from a neglected and underfunded domain of R&D into what is now claimed a trillion-dollar industry, spanning thousands of active companies across almost every continent.

Longevity’s industry four distinct segments/sectors and top startups are:

I) GEROSCIENCE R&D (Science of Aging)

The first segment of the longevity industry is Geroscience R&D, that aims to treat the root causes of aging and is all about: regenerative medicine, rejuvenation biotechnology, gene therapy, nutraceuticals, geroprotectors and of course basic research on biology of aging.

As we age the cells in our body divide until they reach what is known as the Hayflick limit — the number of times a normal human cell population will divide before cell division stops —  which is typically about 50 divisions. When this limit is reached, cell programmed cell death or destruction by the immune system follows for these cells. However, a very small fraction of cells evade this fate to linger indefinitely and become senescent cells, that is secreting a potent mix of molecules that triggers chronic inflammation, damages the surrounding tissue structures, and changes the behaviour of nearby cells for the worse. And this appear to be one of the root causes of aging, causing everything from fibrosis and blood vessel calcification to localized inflammatory conditions such as osteoarthritis to diminished lung function.

Companies targeting these senescent cells (the so called zombie cells) are: Unity Biotechnology, Ichor Therapeutics researching senolytics (drugs to combat senescent cells), and SIWA Therapeutics working on an immunotherapy approach to the problem of senescent cells.

In recent years, two senolytic drugs that have gained mainstay research traction are rapamycin and metformin.

Originally extracted from bacteria found on Easter Island, rapamycin acts on the m-TOR (mechanistic target of rapamycin) pathway to selectively block key proteins in growth. Currently, rapamycin derivatives are widely used for immunosuppression in organ and bone marrow transplants, but research now suggests that using rapamycin results in prolonged lifespan, enhanced cognitive and immune function.

resTORbio (TORC) a spinout from Novartis, is attempting to commercialize a drug platform (RTB101) that inhibits the mTOR pathway and results of the drug’s recent clinical trial include decreased incidence of infection, improved influenza vaccination response, and a 30.6% decrease in respiratory tract infection.

Metformin is a medicine that doctors prescribe to help control blood sugar in diabetic and sometimes pre-diabetic patients. Metformin became a popular Silicon Valley drug because of its anti-acing potential, by increasing the lifespan of mice and bacteria in laboratory studies. Researchers have found that metformin reduced oxidative stress and inflammation —  which otherwise increase as you age —  indicating a strong evidence that can dramatically mitigate cellular senescence by reducing both oxidative stress and inflammation. But another study found a downside of metformin. While it’s in your system, you don’t get any benefit from the exercise you’re doing, to not to mention that metformin also permanently alters your ability to absorb vitamin B12.

Beyond cellular senescence, certain critical nutrients and proteins tend to decline as a function of age, so nutraceuticals combat aging by supplementing and replenishing these declining nutrient levels. For example, NAD+ exists in every cell, participating in every process from DNA repair to creating the energy vital for cellular processes. It’s been shown that NAD+ levels decline as we age. For that reason The Elysium Health Basis supplement aims to elevate NAD+ levels in the body to extend one’s lifespan. Elysium’s first clinical study reports that Basis increases NAD+ levels consistently by a sustained 40%.

As you age your telomeres’ length shortens. Progressive shortening of telomeres leads to senescence, apoptosis, or oncogenic transformation of somatic cells, affecting the health and lifespan of an individual. Shorter telomeres have been associated with increased incidence of diseases and poor survival. A company that is creating research-based clinically tested (randomized, double blind, placebo controlled study) wellness supplements (TA-65) that help address cellular aging through the science of telomerase activation is T.A. Sciences, that claims to have developed a pill to increase the activity of an enzyme (telomerase) that increases telomere length.

TA-65 is a dietary supplement based on an improved formulation of a small molecule telomerase activator that was discovered in a systematic screening of natural product extracts from traditional Chinese medicines.

There are hundreds other companies working on various forms of regenerative medicine and here are some to keep an eye on: for example Osiris Therapeutics Inc. (OSIR) researches, develops, manufactures and commercializes regenerative medicine products intended to improve the health and lives of patients and lower overall healthcare costs. Unlike many early-stage pharma companies, Osiris is actually turning a profit from this.

The second longevity sector is:

II) P4 or the four “P”MEDICINE (Personalised, Precision, Preventive and Participatory)

The first and second “P” in P4 medicine stand for personalised (diagnostics, biomarker analysis, prognostics, in vivo and in silico drug design) and precision, which refers to the drugs and treatments that will be designed and applied using individually-tailored methods. The third “P” in P4 medicine is about prevention and a shift away from reactionary treatment and towards optimized disease prevention long before the underlying pathology develops into actual chronic disease. The fourth “P” in P4 medicine stands for participatory, which refers to the increasingly active role that patients are taking in managing their own health.

Insilico Medicine, a personalised in silico drug design, is the face of AI drug discovery in cancer, Parkinson’s, Alzheimer’s, sarcopenia and geroprotector discovery. ISM has developed a drug discovery and repurposing platform that they refer to as GeroScope that evaluates differences in signaling between “young” and “old cells and tissues and simulates the activity of thousands of known drugs and drugs combinations and assigning geroscores.

One particular use for AI in biology is deep aging clocks. Deep aging clocks are trained on large samples to predict human biological age using different data types, such as: pictures, videos, voice, blood biochemistry, gene and protein expression, and MRI. In a study recently published in iScience, Harvard and Insilico Medicine scientists used thousands of whole genome sequencing samples from gut bacteria to develop and validate a new deep microbiomic aging clock. This new tool indicates that the age of the host is a significant contributor to the gut community dynamics.

Human Longevity Inc is also a personalised and preventive health company, using AI and genome sequencing. Its product, Health Nucleus, involves applying machine learning to provide personalised health assessments from a person’s DNA sequence, as well as a battery of tests that include a whole-body MRI. They want to create a preventive healthcare model that can take baseline measurements of healthy individuals — with its large sequencing, 7-Tesla ultra-high-field magnetic resonance imaging (MRI) and molecular profiling capabilities — and monitor these individuals for life (every 6–12 months), in order to predict and prevent different pathologies. Sounds intelligent, interesting but expensive for now. The company had been valued initially as high as $1.6 billion but in 2018 HLI’s worth dropped by 80%.

Direct competitor of Human Longevity is Alphabet’s secretive anti-aging startup Calico. Larry Page described Calico as a company focused on health, well-being and longevity. Calico’s stated goal is to harness advanced technologies to increase our understanding of the biology that controls lifespan in order to devise interventions that enable people to lead longer and healthier lives. In an announcement Calico revealed one of its in development drugs related to a class of compounds called P7C3s, which appear to protect nerve cells in the brain from dying by activating an enzyme called nicotinamide  phosphoribosyltransferase that inhibits cell death. While Calico remains secretive, its alliance with AbbVie shows Calico is serious about developing marketable products to tackle major diseases in a reasonable timeframe.

III) THE AGETECH MARKET

The third segment of the Longevity industry is AgeTech, which broadly refers to all IT and digital technologies (nextgen mobile apps and fintech for the elderly) that help to maintain greater functionality into older age, and that improve quality of life using non-medical means. This segment also includes advanced and progressive forms of social care (novel retirement plans), as well as products and services that help to preserve neuroplasticity into older ages (entertainment for the elderly, continuing education, cognitive enhancement).

AgeTech can not slow down biological aging, but it can improve the quality of life, enhance psychological well being, mental functioning and neuroplasticity, and increasing levels of independence and social activity. And who knows, maybe in the future we might notice an IT placebo effect from using these IT gadgets…, after all “belief is a powerful drug”.

Alexa Amazon has been identified as one of the AgeTechs to watch which may become a key platform for independent living for many seniors. TrueLink, LiveWell and PensionBee are examples at the intersection of fintech and agetech, offering retirement and other financial services products oriented around the needs of older adults. BrainHQ offers online mental exercises to promote memory and brain health. In robotics associated with aging we have Intuition Robotics and Ageless Innovations. Companies tackling the future of care, are Honor and Sense.ly.

The 2020 agetech market map can be found here.

Longevity United is a data Longevity-focused consumer-oriented mobile app marketplace and ecosystem fueled by the Longevity crypto token that has just established a joint venture with Eterly Inc. Eterly is the world’s first longevity-focused HealthTech mobile app backed by real science. By leveraging AI, blockchain and the marketplace ecosystem being developed by Longevity United, they plan to make an immediate and lasting impact on extending healthy longevity.

And finally the last and fourth sector of longevity is:

IV) LONGEVITY ADVANCING FINANCIAL INDUSTRY

The fourth sector of the Longevity Industry is the Longevity Financial Industry, which encompasses all the activities and efforts of large financial institutions to neutralize the economic issues of aging population (silver tsunami), manifest the opportunities of Healthy Longevity, and enter new markets of AgeTech and WealthTech relating to the one billion people on retirement globally. In the coming years, this sector will become dominated by: Longevity index fund, longevity hedge fund, longevity stock exchange, agetech bank, longevity derivatives and longevity trust. The top 150 financial institutions participating in Longevity industry are highlighted here.

Many of the financial reforms described in this sector can realistically only be implemented in progressive countries lead by technocracy-driven governments, such as Switzerland, Singapore, and the United Kingdom with its detailed industrial strategy.

As elders live longer and healthier lives, novel possibilities open to potentially turn longevity into an asset for society.