Breaking the Dam

Photo: iStock.com/kate_sept2004

After decades of relatively steady increases in life expectancy in many developed countries, including the United States, the United Kingdom and several European countries, recent events have caused an unwelcome pause. In the 2010s, the rise in deaths of despair caused improvement to stagnate, and the impact of the COVID-19 pandemic led to declines in life expectancy since 2019 around the world. Such dismal news has overshadowed a quiet revolution over the last 20 years in the scientific understanding of the fundamental mechanisms of aging. Over time, this revolution has the potential to overcome the current stagnation and resume the upward trajectory of life expectancy, possibly at a much faster pace than we’ve previously seen.

In recent years, scientists have identified roughly a dozen “hallmarks of aging,” or biological factors that cause aging. Research has shown that accentuating such hallmarks speeds up aging, while therapeutic interventions targeting the hallmarks can slow (and potentially stop or reverse) the process. Recent progress in understanding these hallmarks has opened new areas of research to impact them. (Dr. Richard Faragher, a coauthor of this article, shared some of his own research and observations at the SOA Living to 100 Symposium in January 2023.¹) This research is critical to actuaries, as success may mean unprecedented increases in life expectancy, health span (the part of a person’s life spent in good health) and even maximum lifespan. Success may also bring about a step change in medical care, moving from the current paradigm of treating one disease at a time to a more holistic set of treatments that simultaneously target multiple diseases and conditions.²

Research and Clinical Trials

Examples of hallmarks include genomic instability, epigenetic alterations, chronic inflammation and cellular senescence.³ Focusing on just one of these, senescence refers to the finite capacity of an organism to replace lost cells. Initially discovered in the 1960s as a laboratory phenomenon that limited the capacity of populations of normal human cells to divide in tissue culture, the strongest evidence that cell senescence causes human aging came from patients with the rare genetic disease Werner’s syndrome.⁴ Patients with this disease have combined pathologies in many tissues that are highly reminiscent of those seen in normal human aging with a tremendous acceleration of cell senescence in tissue culture. However, this is absent in cultures made from tissues that appear to age normally in the same donors.

Direct demonstration that the accumulation of senescent cells causes aging was provided by the development of a strain of mice that contained genetic constructs that allowed senescent cells to be killed by the addition of a simple chemical compound to the animal’s drinking water. Removing senescent cells greatly improved the health of the mice and increased their maximum lifespan between 25% and 37%.⁵

Attempts to duplicate in humans the type of senescent cell removal studies applied to these mice are moving fast. This requires the identification of senolytics—easily delivered compounds that selectively kill senescent cells. An ever-expanding list of senolytics is becoming available, with the two compounds first discovered (Dasatinib and Quercetin) being used in multiple clinical trials.⁶ While roughly 90% of clinical trials fail, there have already been successful outcomes from two human senolytic trials, and the sheer number being planned means that further success is only a matter of time. What form these will take and which senolytics will be used to treat different conditions remain open questions. Other compounds that reverse senescence rather than killing senescent cells are also available, adding a potentially useful alternative strategy for dealing with them.⁷

One drawback of standard clinical trials is that they often measure only a few “endpoints.” For example, a clinical trial of a drug meant to lower cholesterol may measure just a single outcome: the level of cholesterol. With the type of compounds being tested in hallmark-based trials, researchers would like to measure the rates at which patients develop multiple age-related pathologies over a short time as a proxy for extended healthy lifespans in the long term.

To that end, the Targeting Aging with Metformin (TAME) trials represent a potentially groundbreaking effort. TAME is envisaged as a series of six-year clinical trials at 14 leading American research institutions that will recruit more than 3,000 individuals between the ages of 65 and 79, each with a single stable initial age-related pathology. Unlike normal trials, TAME will measure the time to onset from any first pathology to any second pathology and is expected to demonstrate that the intervention being tested (in this case, the diabetes drug metformin) has slowed down this conversion and effectively slowed aging. A successful outcome may pave the way for Food and Drug Administration (FDA) approval of drugs that target mechanisms of aging generally rather than specific diseases.⁸

Such developments have not gone unnoticed in the for-profit and charitable sectors, and vast amounts of money are flowing into various efforts to understand and “treat” aging. For example, the Saudi Arabia-based Hevolution Foundation recently launched its first funding calls. With an investment of $1 billion per year for the foreseeable future, Hevolution is a nonprofit organization that provides grants and early-stage investments to support research and entrepreneurship with the explicit goals of increasing access to therapeutics that extend healthy lifespan, compressing the time it takes to develop them and maximizing the number of safe and effective treatments entering the market. Several specific venture capital funds, including Juvenescence, the Longevity Vision Fund and Cambria Biosciences, have also supported a raft of startups in the longevity technology space. The cellular reprogramming company Altos Labs reportedly raised approximately $3 billion in funding from Amazon founder Jeff Bezos and ARCH Venture Partners, among others.

Game-Changing Potential

Significant roadblocks still need to be addressed as researchers attempt to translate the results from lower animals to humans. The relative impact on life expectancy and lifespan of targeting any given hallmark will likely vary widely across species. Potential side effects may preclude the use of some treatments. Finally, even for the most promising treatments, the process of designing, funding and running clinical trials in pursuit of FDA approval is lengthy and expensive (the cost of developing a new drug is somewhere between $1 billion and $3 billion, which explains the enthusiasm for “repurposing” drugs, such as metformin, which have already been developed and licensed). While the time scale and ultimate degree of success of such efforts are uncertain, we should expect continued progress in the near future with the real potential for truly game-changing successes.

To illustrate this, we reviewed the impact on mortality of some of the best-known and most comprehensive studies on mice. We created simple scenarios assuming the results of these studies roughly translate to humans. Rather than presuming that particular results fully translate, the published outcomes are taken as a basis for defining a scenario, acknowledging that multiple interventions may be needed to achieve a similar improvement in human mortality. These scenarios are meant to provide a sense of the magnitude of the impact we could see. The continued progress in understanding the mechanisms of aging and the development of treatments to address them may lead to outcomes well beyond these simplistic scenarios.

In Figure 1, we set out three scenarios using two primary scientific studies on mice—one based on targeting cell senescence and the other on the identification of genetic variants that naturally extend lifespan—and representative assumptions around translation from laboratory to human populations. Figure 1 illustrates how these scenarios would affect the life expectancy of a 65-year-old female and present value of payments of an immediate life annuity using a 4% discount rate.

Note: Life expectancies are calculated based on U.S. Social Security life tables and mortality improvements, for illustration.

Applying the outcome of these scenarios to current U.S. single-employer defined benefit pension fund balances of $2.7 trillion¹² produces an increase between $215 billion and $675 billion. The equivalent increases for the United Kingdom’s liabilities (currently £1.5 trillion) would range from £120 billion to £375 billion.¹³

Implications for Actuaries

The ongoing revolution in the science of aging has the potential to produce an unprecedented increase in longevity. While the magnitude and timing of such changes remain highly uncertain, we believe it would be naïve to assume the impact will not be significant. Therefore, actuaries should monitor indicators that may signal a shift in the future trajectory of life expectancy and consider how the risk associated with guarantees of lifetime income can be managed through product design and other means.

Actuaries also can play a role in influencing the scientific community to consider specific questions that would help actuaries and policymakers assess and manage the risk and opportunity of significant increases in longevity and health span.

The first opportunity for the profession to do this is opening now in the United Kingdom. After the publication of an influential report from the House of Lords Science and Technology Committee, U.K. Research and Innovation (UKRI), the national funding agency supporting science and technology research in the United Kingdom, has supported the formation of a series of networks addressing multiple aspects of aging in the hope of accelerating U.K. progress in this area. Later this year, the Building Links in Aging Science and Translation (BLAST) network will directly address this and other industrial questions and priorities through a dedicated workshop on the business case for aging research.

Statements of fact and opinions expressed herein are those of the individual authors and are not necessarily those of the Society of Actuaries or the respective authors’ employers.

Copyright © 2023 by the Society of Actuaries, Chicago, Illinois.