The Current State of Longevity Science

AI will accelerate real-world implementations of Longevity Science, enabling a paradigm shift from Precision Medicine to Precision Health.

My three previous articles on the Longevity industry raised a great deal of interest. Some thought that my projections were too bold, while others (including several scientists who work in the field of Geroscience) thought that my projections were too conservative and that our article seemed overly skeptical about current progress in aging research. In this article, I'll take a deep dive into the current state of Longevity Science, with an emphasis on practical applications and recent scientific progress. I'll explain why investors may underestimate the current rate of progress, why scientists may overestimate the current rate of progress.

Some may not think of it as such, perhaps still equating progress in Longevity with linear progress in geroscience, or perhaps as a combination of geroscience and the application of regenerative medicine to aging. But even this view is outdated. In the past decade, the combination of technologies that will escort the global population to longer, healthier, more productive lives has expanded and diversified. The Longevity industry has advanced well beyond geroscience and now occupies a point of convergence between digital, biotechnological, and financial technologies, working together in various ways through governmental coordination across the globe.

Digital Transformation

Biomedical research is facing a similar digital transformation, with data science and AI revolutionizing and accelerating testing. Before long, anything related to aging and Longevity will consist of a rapid succession of precisely calculated micro-interventions (e.g. micro-dosages) administered in response to continuous monitoring of fluctuations in biomarkers of aging in order to restore them to normal levels long before the actual onset of disease. The rate of progress in aging research is currently limited by a reliance on the use of model organisms to assess the safety and efficacy of therapeutics. But when dealing with aging, this method will become increasingly ineffective due to the vast genetic difference between the aging processes in model organisms and humans, as digital technologies allow for the possibility of a more rapid human-centered approach to testing.

Biomarkers

In medicine, a biomarker is a measurable indicator of a biological state or condition. In practice, biomarkers are used to measure the severity or presence of some specific disease state, and can be used in disease diagnosis and prognosis. Biomarkers are used in numerous kinds of research, both in vitro and in vivo, and almost always include human studies. Although individual biomarkers are difficult to classify, scientists nonetheless identify three specific types: exposure biomarkers, effect biomarkers, and susceptibility biomarkers. These can be used as indicators for several purposes. For example, a biomarker can confirm or disprove the disease risk in an individual, or negative effect which pathogenic agents or their metabolites, chemicals or organic substances have caused. Or, biomarkers could reveal an individual’s sensitivity to specific effects of treatments, and thereby provide the necessary advice for future treatments.

Digital Biomarkers

Biomarkers are typically classified as molecules which have properties that allow them to be measured in biological samples in clinical settings. But what if we measure people's health outside the clinic with the help of everyday devices such as a phone? Thanks to advances in digital technology we now have access to a whole new form of measurable indicator: digital biomarkers. Digital biomarkers are like any other biomarker, but measured through gadgets.?Digital biomarkers are defined as objective, quantifiable physiological and behavioral data that are collected and measured by means of digital devices such as portables, wearables, implantables and digestibles. This data can be used not only to confirm the presence of any kind of disease but to predict and, moreover, prevent all possible pathologies.?

Nowadays digital biomarkers are widely studied in order to reveal the broad spectrum of possible uses, and to revolutionize current methods of patient health state monitoring and disease outcomes prediction. According to Digital Biomarkers Journal, a multidisciplinary-by-design open access journal that bridges the disciplines of computer science, engineering, biomedicine, regulatory science and informatics, digital biomarkers represent an opportunity to capture clinically meaningful, objective data.

Digital biomarkers could be the breakthrough bioscience has been waiting for, which is why not only individuals and health care providers but also many companies have grabbed the opportunity with both hands. Breathometer, Xsensio, Scailyte AG, Nightingale Health, FEET ME, xbird, Mindstrong Health, Serimmune, IXICO, etc., are top private companies that successfully carry out the mission of digital biomarker popularization. They are known for the development of unique sensing platforms and chips, human liquid testing systems, devices for health monitoring, single-cell profiling devices, and providing unique information that fuels development of new diagnostics, vaccines, and therapeutics. All of these enable novel approaches for preventing and treating a great many diseases.?

Digital biomarkers could potentially reorganize the whole Pharma industry and become an integral part of the drug development process. Due to the sensitivity and precision they provide, digital biomarkers can be used to improve clinical trials of drugs. While testing a treatment, finding the appropriate dosage, and looking for side effects, this new form of indicator reveals a drug's efficacy and toxicity for individual patients.

In 2017 the Digital Biomarkers Journal provided a deep analysis of the modern pharmaceutical business model and how it implements digital biomarkers. According to the article, in the case of some illnesses, digital biomarkers can improve the understanding of the natural history of a disease through more continuous measurement of objective health data. Such information may become priceless in situations where symptom presence and severity is more variable and disease prevention and treatment necessitates a more individualized approach to each patient. The past few years have seen increased interest in digital biomarkers and in expanding the scope of their application. I expect that digital biomarkers will eventually become routine in patient care.

What are aging biomarkers?

Aging is a major risk factor for most chronic diseases and functional impairments. Within a homogeneous age sample there is considerable variation in the extent of disease and functional impairment risk, revealing a need for valid biomarkers to aid in characterizing complex aging processes. The identification of biomarkers is further complicated by the diversity of biological living situations, lifestyle activities and medical treatments. Thus, there has been no identification of a single biomarker or gold standard tool that can monitor healthy aging.

How do we know when a biomarker is a biomarker of aging? It depends on how it is sourced. The current approach to biomarkers is to take them from people at various stages of a disease’s known progress, which in practice means sourcing them from hospital patients. Isolating biomarkers of aging, however, means collecting data which marks the difference between healthy people only, e.g. between the young and even younger, with no traces of any officially recognized diseases.

The diagnostic technologies of the future should be anchored to panels of aging biomarkers digitally obtained. This will enable the current state of health of each patient to be continually and precisely monitored, allowing the effectiveness of interventions and micro-adjustments to interventions to be continuously assessed in detail, enabling an unprecedented degree of precision and prevention in biomedicine, and an unprecedented degree of prescience in biomedical research.

It is important therefore to develop and promote the widespread use of a panel of biomarkers which are not only comprehensive but also immediately actionable. A panel of less precise but easily implementable biomarkers of aging would be much better than an extremely precise and comprehensive panel of biomarkers of aging that is too hard or expensive to translate easily into widespread practical use across nations.

As an example of minimum viable biomarkers, consider that a set of of aging biomarkers was developed recently which is based on Deep Learning analysis of standard blood biomarkers, which is less accurate than the most precise available biomarkers of aging (DNA Methylation clocks), but which is nonetheless good enough, and can be implemented by any researcher, doctor and clinician that has access to routine blood tests.

As a further example, consider that biomarkers of aging have been constructed using Deep Learning-based analysis of photographs of mice, which could quite easily be extended to humans. Their accuracy alone is not enough to make them a research priority, but the increasing video capabilities of smart-phones means that these rapid development of photographic biomarkers of aging (e.g. of the face or the eye) could now be a very actionable area of research whose practical level of precision and accuracy will develop quite rapidly in coming years.

Gathering aging biomarkers means collecting data which marks the difference between healthy people only, e.g. between the young and even younger, with no traces of any officially recognized diseases. The continuous monitoring of small changes in such biomarkers, and the continuous and commensurate micro-adjustment of treatments in response, allows for some de facto reversal of biological age.

Most Promising Domains of Geroscience

Aging Analytics Agency monitors each domain of geroscience closely. The following are some of the research areas, people and organizations to put on one’s watchlist if one wishes to get an overview of which are progressing the fastest. Also added are a few words about the rate of progress of each, and the difficulties currently faced by each going forward.

Senolytics

Senescent cells, also known as “zombies cells”, are cells that refuse to die well after they are due to be replaced. Scientists believe that they speed up aging and create favorable conditions for pathologies when they build up in our body. A major interest of gerontologists is creating specific and low side-effect drugs that can induce death of senescent cells, referred to as senolytics. The aim of senolytic research is to prevent or delay age-associated conditions, and many known potentially senolytic drugs are under intensive investigation.?The main difficulty for finding remedies to this obstacle is that the science behind cellular senescence is not yet completely understood. The link between cellular senescence and aging needs to be further researched.

Geroprotectors

Geroprotectors are chemicals with the ability to slow down aging and age-related diseases. Usually, they achieve this through interplay with the key aging-associated signaling axes in cells. Two of the most well-known geroprotectors, rapamycin and metformin, have already been validated extensively in model organisms. The challenge that remains is for gerontologists to find natural mimetics of validated synthetic drugs. The reason for this is that natural occurring mimetics should be less toxic and more bioavailable. This makes geroprotectors a very promising field of aging science and pharmacology industry. Of all the domains listed here geroprotectors are the closest to practical implementation with several examples of real-world use even today, many functioning as natural mimetics of various `tried-and-tested substances such as metformin.

Gene therapy

Gene therapy is precision treatment for fixing deficient genes. It is achieved through editing genes by delivering replacement genetic code to cells packed inside viruses. This can be done to germ cells as well as with adult organisms. Multiple systems of gene editing have been developed and the most recent - CRISPR - is a major subject of media hype and scrutiny. The potential of gene therapy is vast and its possible uses innumerable. In particular it is an eventual key component in rejuvenation biotechnology, mentioned below. Anti-aging gene therapies had received a great deal of publicity in recent years and has made headlines with its various lurches forward. Prominent Harvard geneticist George Church, via his company Rejuvenate Bio, has recently delivered 45 gene therapies to provide aging reversal and found the combined treatment effective against obesity, diabetes, osteoarthritis, cardiac damage and kidney disease. They expect to get the treatment in the hands of actual patients by around 2025.

Cell therapies

Stem cell therapy is used to regenerate tissues and organs. There has already been some reported success in regenerating seriously damaged tissues and organs. Cellular therapies also include personalized cancer treatment by modified T-cells, also known as CAR T-cell therapies. The field is now booming and in 2018 a Nobel Prize in relevant T-cell research was received by James P. Allison and Tasuku Honjo. Several CAR T-cell therapy products have been approved by the FAD already. Over 240 CAR-T clinical trials are running. The field of immuno-oncology is attracting billions of dollars in investment and a great deal of interest from pharma. Transplantation of therapeutic stem cell populations could be used to treat a number of diseases, such as blindness, muscular dystrophy, myocardial infarction, stroke, missing teeth, wounds, Alzheimer’s disease, and so on. There were 33 ongoing phase III clinical trials of cell therapies and 16 of gene-modified cell therapies, including CAR T-cell therapies, at the end of 2018.

Caloric restriction mimetics

Calorie restriction (CR) mimetics is a class of drug candidate that can mimic the anti-aging effects that occur naturally due to a decrease in calorie intake of 20-50%. This process happens without any harmful side-effects such as malnutrition. It works by targeting key signaling pathways such as the rapamycin pathway. Today, there are no validated CR mimetic drugs for human consumption, but this field under intensive investigation. This explanation for the huge interest in this domain is that calorie restriction has already been shown to extend the lives of various laboratory organisms - from yeast and nematoda to rodents. CR mimetics is being thoroughly investigated, but the field holds limited promise in humans.

Regenerative Medicine

Regenerative medicine is the repair of damaged (or aged) tissues and organs, e.g. by regenerating human cells, artificially engineering tissues and organs to renew their functionality, and regrowing and repairing damaged, lost or aged cells, tissue or organs. The application of regenerative medicine to aging is called “rejuvenation biotechnology”, the most fully elaborated strategy for which is SENS (Strategies for Engineered negligible Senescence), an action plan for repairing aged tissue based on a “damage report” consisting of a list of manifest differences between old and young cells and tissues.

A typical example of a problem of aging amenable to regenerative medicine solutions would be stem cell exhaustion. This can reduce the efficiency of the immune system, and lead to muscle loss, a decline in bone mass and slow wound healing. A solution to this obstacle, therefore, could significantly extend healthspan. A regenerative medical solutions would be to find a way to enhance the activity of stem cells. The difficulty with this approach are also typical of regenerative medical solutions: it can lead to unwanted side effects, as the stem cells can senesce at an accelerated rate, resulting in premature aging. Slowing their activity, on the other hand, can cause premature aging as well. There’s a clear need, therefore, for finding the “sweet spot” for stem cell activity and guiding the cells in that direction. We also need further development of effective tools to operate on stem cells in the tissues and either replace or rejuvenate them.

Ovarian rejuvenation

Menopause negatively affects women's lives as it leads to a hormone imbalance and a number of associated problems. Headaches, racing heart, urinary urgency, and weight gain are only some of those. But women always have eggs inside their ovaries (even during postmenopause). A lot of eggs just stay dormant. Ovarian rejuvenation is a new approach to re-awake egg maturation and development. Its could lead to a more normal physical and mental state in 40+ women by removing menopause and postmenopause symptoms. Also, it could slow down aging by keeping hormone balance typical for reproductive years. All-in-all it could decrease the number of woman’s disability-adjusted life years as it allows them to maintain health and wellbeing. Modern approaches to ovarian rejuvenation include PRP (Platelet Rich Plasma) injections, and injections of the patient's own fat stem cells directly into the ovaries.

Immune System Rejuvenation

People of advanced age frequently face immune dysfunction in their innate and adaptive?immune systems. This type of age-related condition is known as immunosenescence. This leads to chronic inflammations, chronic diseases and higher rates of infection. The task of immune system rejuvenation is to stimulate and support the indigenous immune system to restore and maintain its optimal, youthful functionality. Established rejuvenation practice include stem cells recovery,?thymus rejuvenation, and modulation of hormone production. Immune system rejuvenation is relatively far from practical implementation, but with some low hanging fruit, e.g. people are already experimenting with altering their own immune system through fasting, so there is a great deal of experimental data is easily obtainable.

Inflammaging

Aging impacts how cells communicate with each other, which can cause inflammaging: a constant state of low-level body-wide inflammation, which in turn brings about several aging-related conditions. Countering inflammaging would improve the immune system’s activity and could mitigate many aging-related conditions. Cells communicate with each other by sending chemical signals of various kinds. This ability is one respect in which aging can be a “contagious” process, for example how senescent cells can urge other cells—even in other tissues—to undergo senescence themselves. Senescent cells release pro-inflammatory molecules that contribute to a general state of inflammation in the body. This condition is associated with aging and many aging-related diseases including Alzheimer’s, atherosclerosis, Type II diabetes, and cancer, and can hinder the function of adult stem cells. Constant inflammation can even accelerate telomere attrition, which then promotes cellular senescence.

Biogerontology?

Basic research into the biology of aging.?Although those with a more utilitarian approach to gerocience would prefer to prioritize translational research rather than the pursuit of a fully?comprehensive theory of how aging occurs, theoretical biogerontology still has much to achieve, and is likely to hold unforeseen promise. It has already proved essential to the kind of intelligence gathering which enables interventions in other domains listed here such as senolytics and mimetics, and it is impossible to tell what new doors further research may uncover. Biogerontology has in its sights the eventuality of a “robust theory of aging”, a theory that ties together all the different mechanisms of aging and explains the relationship between them. The theory would predict how any change of the involved factors will affect the aging process. The development of such a theory would prove audacious but impactful, and a proof of concept is expected around the year 2030.

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This article was written by?Margaretta Colangelo.?Margaretta is Co-founder and CEO of?Jthereum an enterprise Blockchain technology company. She is associate editor at AI Time Journal and serves on the advisory board of the AI Precision Health Institute at the University of Hawai?i?Cancer Center. She is based in San Francisco.?@realmargaretta