Biomedical Applications for Human Longevity (1)
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 the research for my master’s thesis at the chair for strategy and organization of professor Isabell Welpe at the Technical University of Munich (TUM).
In Part 1, I provide an introduction to the topic and describe biomedical applications targeting four of the nine causes of cellular aging, or the four primary hallmarks.
In Part 2, I present biomedical applications targeting the other five causes of cellular aging — antagonistic and integrative hallmarks — and discusses the future development of human longevity as paradigm for the pharmaceutical industry.
Why We Need to Understand Aging
Doubling human life expectancy within the last century was an incredible achievement. Increase in life expectancy is one of the most universally accepted indicators for human progress. Eradicating infectious diseases, greater hygiene, and richer nutrition all played pivotal roles. But longer lives are not just an output. More people living longer and more safely allows for more scientific discoveries to be made, innovative business ideas to be tried out, and for ever more creative expressions on the human experience to be shared through the arts.
And yet thinking of a long life and old age, people tend to worry. They fear the loss of autonomy and purpose, the increasing social isolation, and a myriad of pills and therapies associated with age-related illnesses. Cardiovascular diseases and cancer are the two leading causes of years spent with disability accounting for 25% among all causes including accidents and armed conflict. By 2030, 21% and 32% of the population in the United States and Germany will be 65 or older compared with 15% and 24% in 2015. At the same time, the global number of patients with dementias, an uncurable condition, is expected to increase by 60% to 82 million. The medical profession and regulators acknowledge that to continue serving their patients and constituency they need to further improve healthcare for age-related conditions.
Drug development may be the most powerful lever for improvements. Currently, senior patients disproportionately contribute to healthcare costs. In the United States, for example, people 55 and older (29% of population) account for more than 50% of health expenditures. But while populations age slowly, the main driver of rising healthcare costs likely is the persistently declining productivity in pharma R&D. Between 1950 and 2000, the average cost to develop a single drug to regulatory approval increased hundredfold in the United States. There are certainly many achievements to celebrate. More than 120 therapies for cancer, for example, received regulatory approval between 1980 and 2018. But at the same time only five therapies for Alzheimer’s disease gained approval and none provides a cure. Individuals’, insurances’, and governmental budgets are unlikely to bare significant further price increases at the same level of coverage and service as today. More so, as relatively more individuals move from work to retirement in the coming decades refinancing on the system level will become more difficult.
How we age
Focusing on aging as an upstream target rather than individual age-related diseases may be the most significant shift ahead to improve pharmaceutical productivity. Aging is considered as a natural process. All forms of life age and eventually die but at very different rates. Some species of turtles and whales can live more than 200 years, some jellyfish are even considered immortal. Aging researchers think that the cellular and molecular events of aging are reversible. Aging to them is the accumulation of damage and the loss of information. With sufficient understanding, both could be undone, and aging would be only a few dozen conditions instead of hundreds of illnesses requiring separate therapy. The FDA already approved muscle weakness and obesity as treatable conditions. Treating both averts multiple downstream illnesses from diabetes to cardiovascular diseases, arthritis, organ failure, and many others. Focusing on aging promises to yield fewer but more effective treatments.
A seminal step into this direction was the 2013 publication of “The Nine Hallmarks of Aging”, a research paper in the journal Cell cited more than 6,000 times by mid of 2020. The hallmarks are the nine reasons why we age on the level of cells and molecules. How the hallmarks interact and work exactly to produce different diseases is still incompletely understood. Several biotechnology companies focus their development on one or multiple of these nine hallmarks. Solving one hallmark in a therapeutic area like cancer promises treatments for multiple types of cancers.
According to my research, more than 150 companies as of 2020 are actively developing therapies and diagnostics for human longevity. Since 2013 new companies were added to the industry at a rate of 40% every year. More than 100 of the total develop in the United States. The emerging industry received around US$ 6.5 billion in funding. 12 more advanced, clinical stage companies aggregate 80% of the funding. Alphabet’s Calico is leading by a great margin with US$ 2.5 billion. The majority of companies are still in the early phase of drug development and have not received any significant funding.
Applications for Primary Causes of Aging
Many companies which emphasize human longevity in their mission focus on one hallmark. There are three categories of hallmarks — primary, antagonistic, and integrative — which play different roles in diseases and conditions of aging. Primary hallmarks are the four main reasons why we age and the focus of Part 1 of this article. Primary hallmarks are the initial source of damage and should be avoided in any case.
Primary Hallmark #1 — Genomic Instability:The first primary hallmark, genomic instability refers to the accumulation of damage of the DNA with age, most known as the cause of cancer. Damage to the DNA comes in several forms, for example, breaks of the double strand or single faulty base pairs. Liquid biopsy is an innovative approach to identify these mutations in the blood. Cancers secret cells and fragments of DNA into the bloodstream. Taking a blood sample and sequencing the contained DNA allows to detect low levels of residual cancer in tissue inaccessible to traditional and more invasive tissue biopsy. Companies focused on liquid biopsy rely on machine learning and large databases to commercialize testing and health data management as services directly to patients. Diagnosing cancer before spreading can increase the five-year survival rate more than six-fold saving the United States, for example, an estimate US$ 26 billion a year in costs related to cancer. Widespread adoption of liquid biopsies also for cardiovascular diseases and neurodegeneration can help earlier diseases detection. The technique is already commercially available. Further decreases in genome sequencing costs drive the adoption of this technology.
Primary Hallmark #2 — Epigenetic alterations: As we age, the genome accumulates damage but also the machinery that determines which genes are active or inactive — the epigenome. These so-called epigenetic alterations are similar across individuals. Several companies use these changes as measurements for biological age. Japanese scientists Shin’ya Yamanaka received the Nobel prize in medicine for reprogramming a regular cell back into a stem cell by changing its epigenome. Based on his discovery, several companies develop treatments to reverse age-related epigenetic changes but not the cell’s identity. Using this technique called partial cellular reprogramming, an old liver cell, for example, would become a young liver cell (but not a brain cell). Epigenetic changes are an important measurement for the success of clinical trials in aging research. The approach is commercially available. The impact of partial cellular reprogramming is difficult to assess but potentially foundational for a new field of medicine. Variants of the technique could receive approval by 2029.
Primary Hallmark #3 — Telomere attrition: Another albeit less accurate indicator of cell age is the length of telomeres. Telomeres are the protective endings of chromosomes which store the DNA in every cell. With each cell division, telomeres shorten in a planned manner until the cell undergoes controlled cell death. Short telomeres make the DNA more susceptible to damages. Cancer cells abuse this property. They slightly extend their telomeres with a protein called telomerase. This repeated extension makes them immortal, and the incomplete extension allows the DNA in the cancer cell to mutate even more. Several companies develop therapeutics, called telomerase inhibitors, that destroy the telomeres in the cancerous cell. They could, in case of successful clinical trials, be available by 2024. Other companies work on gene therapies to fully recover telomeres for example to treat premature telomere attrition in Alzheimer’s disease. These therapies will receive approval in the United States most likely only after 2030. Other jurisdictions, for example, Columbia scheduled first clinical trials.
Primary Hallmark #4 — Loss of proteostasis: A human cell hosts more than 10,000 different proteins. They are the function of the cell. As enzymes, for instance, they control chemical reactions, as hormones, they send messages to distant cells, and as antigens, they fight attackers like viruses. Having the right proteins ready and functioning in the right amount is vital. With age, our protein production and regulation machine get more and more off beat. This is a characteristic of diseases like Alzheimer’s where aggregates of malfunctioning proteins gradually destroy brain cells. The cerebrospinal fluid surrounds the brain and also acts like a kind of sewage system to transport these toxic protein aggregates away. But with age, the vessels involved in the transport become clogged and the machinery for filtering and degrading the toxic aggregates overwhelmed. Several companies work on devices conceptually similar to a kidney dialysis to improve the function of the cerebrospinal fluid. These devices could with fewer adjustments than therapeutics adapt to different neurodegenerative diseases. Dementias already cost US$ 1 trillion globally expected to double by 2030. Commercial availability is likely later than 2030.
Summary
The presented applications target the four primary causes of cellular aging. They also highlight a few important trends in healthcare. Liquid biopsy and direct to consumer offerings foreshadow a shift to more preventative treatments and stronger patient involvement. Companies and patients moving to other jurisdictions for clinical trials and early access to innovative therapies highlight the importance of greater efficiency in clinical testing and regulatory review. Finally, human longevity as a paradigm could catalyze new therapeutic approaches. These could bring us closer to a cure for diseases like Alzheimer’s after 20 years of failures. This will require at least another ten years in development. Other therapies focusing on hallmarks like senescence and stem cell exhaustion described in the second part are already closer to regulatory approval.
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