Biomedical Applications for Human Longevity (2)
Foreword: This article is one in a series of two on the paradigm shift of human longevity in drug development and on selected biomedical applications. It is a summary of research for my master’s thesis at the chair for strategy and organization of professor Isabell Welpe at the Technical University of Munich (TUM). Originating from a chair for management research, this thesis on biotechnologies is one small proof for the high degree of interdisciplinary thinking that I experienced at TUM.
In Part 1, I provide an introduction to the topic and describe biomedical applications targeting four of nine causes of cellular aging, or the four primary hallmarks.
In Part 2, I present biomedical applications targeting the other nine causes of cellular aging — antagonistic and integrative hallmarks — and discusses the future development of human longevity as paradigm for the pharmaceutical industry.
The primary hallmarks, as the name suggests, are the four primary causes of cellular aging, as presented in Part 1 of this article. Genomic instability, for example, is one primary hallmark that causes cancer. The three antagonistic hallmarks are protective responses to these primary damages. Senescence, one antagonistic hallmark, for example, is a reaction of the surrounding cells to contain the spread of cancerous neighbors. But if unchecked, senescent cells and the two other antagonistic hallmarks — mitochondrial dysfunction and deregulated nutrient sensing — become a cause of damage by themselves.
Applications for Antagonistic Causes of Aging
Antagonistic Hallmark #1 — Deregulated Nutrient Sensing: Deregulated nutrient sensing, the first antagonistic hallmark, concerns the metabolism which is about the creation and degradation of substances. For an individual cell, the abundance of specific nutrients like amino acids signals growth and faster replication. Analogously, the lack of these nutrients initiates the recycling of leftovers inside the cell. These degradation mechanisms serve as important quality control systems. Intentionally reducing calorie intake, can activate them by reducing the activity of a group of proteins called mTOR. In experiments with mice, for example, a reduced calorie intake of 30% correlated with a 50% increase in life span. From an evolutionary point of view, similar increases through inhibiting mTOR are unlikely in humans. Surviving a famine in one year provided a major reproductive advantage for a rodent with a life expectancy of only a few years. Humans with significantly longer life spans would not benefit in the same way from an equal increase.
The effect of having too much calories on human lifespan, on the other hand, is clearer. Obesity is a risk factor for a myriad of diseases and associated with shorter life spans. A study published 2018 in Nature found that for obese men aged 20–29 years life expectancy is reduced by up 10 years. The proliferation of overweight, especially, in young age is worrisome. Obesity among children between the age of five to 19 has increased more than tenfold in the last 20 years; now globally close to one in five kids is overweight. For those aged 60 or older in countries more affected like the US, more than one in three is obese. To extent healthy life via therapeutics, treatments like need to intervene with metabolism.
In the context of aging research, several companies work on drugs that mimic the effect of reduced calorie intake. These inhibit mTOR — a master regulator of metabolism — initiating recycling of waste inside the cell. In cancer therapy, for example, these mTOR modulators are approved but act more like sledgehammers. For chronic treatment, necessary to extend lifespan, drug developers work on something closer to a watchmaker’s toolkit. This means inhibiting not the entire group of proteins but fractions, namely only mTORC1. Leading companies are resTORbio, acquired by Adicet Bio, Emtora Biosciences, and Navitor Pharmaceuticals. Their therapies to slow cognitive decline will become available earliest after 2030.
Antagonistic Hallmark #2 — Mitochondrial Dysfunction: Mitochondria are the powerhouses of the cell producing around 90% of cellular energy. With age, the process behind the energy production, the respiratory chain, destabilizes damaging the DNA — inside the nucleus and the mitochondria. These damaged mitochondria are never repaired but only replaced by the cell. With age, this replacement slows down. The previously described increased activity of mTOR or the attrition of telomeres are just two contributing factors. Fewer capable mitochondria reduce the level of available energy. Organs like the brain or heart with high energy demand are the first to rebel.
The conceptually most straightforward approach is to transplant healthy mitochondria from a donor. This can be achieved for example via stem cells. Mitochondria are injected into stem cells previously extracted from the patient. Once the cells incorporated the mitochondria, they are injected back into the body where they return to their niche. One active developer is the company minovia Therapeutics. A second — and more radical — approach is to relocate gene expression from the mitochondria to the cell nucleus to curb the damage from defective mitochondrial DNA. A gene therapy replaces the defective gene inside the mitochondria with a healthy copy introduced into the cell nucleus. The cell then shuttles the protein to the mitochondria. In case of successful clinical trials, the therapy pursued by the company Gensight Biologics could receive approval by 2024 for a rare form of blindness. Mitochondrial transplantation may follow after 2030.
Antagonistic Hallmark #3 — Cellular Senescence: The last antagonistic hallmark, cellular senescence is one of the most established fields of aging research. Cells that enter senescence stop growth permanently as a reaction to damage in their environment like cancer. They secrete a mix of pro-inflammatory chemicals, called the SASP, that initiates senescence in their neighbors and alerts the immune system. The healthy immune system clears out the senescent cells and coordinates the repair of the tissue. But with age the immune system weakens, and more and more senescent cells stick around. This chronic form is unregulated and causes diseases.
Drug developers focusing on senotherapeutic aim to cure this condition of aging. Their leading approach are senolytic drugs which kill the senescent cell directly through toxic particles. The main challenge here is to limit the damage to surrounding healthy tissue. This could be circumvented with immune therapies, an emerging approach in senescence research. Activating immune cells ensures minimal damage to healthy cells but could ultimately prove less effective with an aged, chronically overwhelmed immune system. Senolytics are more mature and could receive regulatory approval by 2025. The leading developer, the company UNITY Biotechnology founded out of the Mayo Clinic and the Buck Institute, targets arthritis in the knee and eye diseases. The focus of the field is on solid cancers and musculoskeletal conditions like muscle weakness.
Applications for Integrative Causes of Aging
Integrative hallmarks are the result of primary and antagonistic hallmarks. They explain the functional loss of tissue with age. As senescence becomes excessive, for example, the associated chronic inflammation affects intercellular communication and stem cell populations — the two integrative hallmarks.
Integrative Hallmark #1 — Stem cell exhaustion: Stem cells are the predecessors of any cell in our body. Through differentiation they replenish rapidly deceased cells and thereby guarantee the working of the tissue. Stem cells live in different pockets, or niches, across the body like the bone marrow. Stem cells in the bone marrow mostly differentiate into red or white blood cells. With age, stem cell populations can be exhausted for several reasons including chronic inflammation or depletion. Approaches which address stem cell exhaustion can be distinguished into two groups.
The first aim to replace the damaged organs or tissue. Bioprinting, for example, uses a mix of synthetic materials and cells from the patient to produce an individualized replacement. For treatment of skin damage and skin aging, replacements could be available by 2023. A leader is the company LifeSprout. Recreating the network of vessel (vascularization) is the major obstacle for complex organs like the heart or the liver. Xenotransplants overcomes this obstacle. The technique uses genetically modified pigs to grow organs and also individual cells like neurones to treat Parkinson’s. Gene editing ensures the organs are compatible to humans. The two partnering leaders, eGenesis and Qihan Biotech, expect available products after 2030. Commercializing the bioprinting of entire organs will likely take even longer.
The second type of approaches tries to exploit and stimulate the patients intrinsic repair mechanisms. One entry point is the thymus, a small organ responsible for educating immune cells. For reasons not fully understood the thymus undergoes a programmed decline beginning with puberty. Restoring the thymus would strengthen the immune system, which would among others curb senescence, and thereby protect stem cell populations. The startup Intervene Immune uses already approved drugs including growth hormones to stimulate rejuvenation of the thymus. Last year, they reported a 2.5 year rejuvenation. Currently recruiting for a clinical study, their approach could receive approval by 2026.
Also in the second group is a cell therapy which targets lymph nodes. Our body possesses around 500 lymph nodes which are in charge of incubating immune cells. This property makes them attractive for growing organs. The company LyGenesis develops a cell therapy that moves liver cells inside the lymph nodes. There the cells grow into miniature livers that augment the function and healing of the damaged liver. This approach theoretically allows to treat around 75 patients with a single organ transplant and at a significantly lower price compared with regular transplantation or xenotransplantation. In case of successful trials starting this year, the therapy could be available before 2030 for some of the estimated two million patients waiting globally for an organ transplant.
Integrative Hallmark #2 — Altered intercellular communication: That cells can communicate with one another is the foundation for all the complex organisms inhabiting the earth today. Depending on the distance, cells use different mechanisms. Distant cells rely on the blood stream to carry hormones and inflammatory signals. With age, several of these signaling pathways change contributing to age-related diseases. The blood of young organisms seems to differ significantly from that of their grandparents. Experiments combining the blood streams of differently aged mice via surgery, called parabiosis, for example, demonstrated the rejuvenating effect of young blood on the muscles and the brain.
Several teams work to translate these finding into targeted therapies. One of the leading developers, Alkahest, focuses on signals in blood plasma related to aging of the immune system and cognitive decline. Another company, Elevian, addresses so-called growth factors important for cardiovascular regeneration. First therapies could be available by 2024. And some are especially eager. The company Ambrosia, for example, offers a simple transfusion of young blood at US$ 8,000 already but without sound evidence for its effectiveness. Some secretive players like Nugenics report rejuvenation effects of more than 50% through their “Elixir” without providing any details on the ingredients. “Blood is a quite peculiar juice.” said Goethe’s Mephistopheles. It remains to be seen what special role it plays in aging and rejuvenation.
Summary
Part 1 presented applications addressing the primary causes of aging. They outline the greater involvement and autonomy of patients through direct testing, preventative therapies, and medical tourism. Part 2 addresses the antagonistic and integrative causes of aging. Here four findings stand out. One is the growing re-use of already approve drugs in aging research. Re-using drugs approved for other diseases fastens clinical trials. A second insight is the need for public communication in aging research. Communicating to the public and investors that that the focus on human longevity is reputable science and not alchemy is essential to obtain funding and bring about the necessary regulatory changes. Communicating credibly that the focus of drug development on processes upstream to diseases — like the nine hallmarks — promises more efficient development and treatments for complex diseases like Alzheimer’s is essential.
Two forces (the last two findings), are likely to accelerate this transition. The first is the emergence of machine learning platforms which identify and confirm new drug leads for incumbent companies. These drug discovery engines are to a greater extend agnostic to diseases relevant later in the development. Focusing their development on processes of aging maximizes the commercial potential of their discoveries. Their development approach will likely facilitate the shift from individual age-related diseases to aging. Leading companies are InSilico Medicine, Gero, FoxoBio, Calico, or NetraPharma.
Venture capital companies focused on longevity are the second force. These organizations, apart from early-stage funding, provide expertise on IP management and their network. They attract radical biotechnology innovation and ensure that the mission-driven startup develops projects fundable for established pharma companies. Their investments accelerate research and help translate it into treatments that reach patients. Examples of these companies are Juvenescence, Cambrian Biopharma, and also Life Biosciences.
Treating age-related diseases more effectively helps more people to live a longer life without the burden of diseases. The applications are a selection of radical biotechnologies for human longevity. The majority are still early stage, but some like senolytics and blood-based therapies could receive approval already by 2025. Machine Learning and drug repurposing, direct to consumer testing and preventative therapies, together with the changing perception of aging research from governments, investors and the public accelerate their development and commercialization. And even if all of them fail, the ambition to extend human life by radically transforming drug development is here to stay.
Afterword: If you want to learn more about these and other applications, Gonzalez-Freire et al. (2020) provide an in-depth review of different anti-aging interventions. Additionally, the blog by the Life Extension Advocacy Foundation and Reason, a longevity entrepreneur, are great to start reading on the topic and follow major development.
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