MCARD: Measuring Causes of Age-Related Disease

Norn Group

Summary

MCARD envisions an initiative encompassing technology development and clinical collaboration, with the goal of finding therapies that treat multiple diseases of aging at once and giving them a validated path to approval.

At the heart of MCARD’s mission is the search for biomarkers that measure the biology driving age-related diseases such as cancer, stroke, and Alzheimer’s disease.

MCARD aims to include these biomarkers in every United States clinical trial in order to evaluate the potential of new disease treatments to target multiple diseases of aging.

The world is aging…

By 2029, the United States is projected to have more old (65+) people than children [1], and the global elderly population will double current numbers by 2050 [2]. Advanced age is the greatest risk factor for most severe disease outcomes in developed countries, including neurodegeneration, cancer, and COVID-19 [3, 4]. The number of people living with dementia worldwide is expected to nearly triple by 2050 [5], as is the number of Americans with Alzheimer’s disease dementia (Figure 1) [6], and similar projections for other symptoms and diseases of aging add up to a terrifying healthcare burden: two thirds of the ballooning 65+ population suffer from two or more chronic diseases at the time of writing [7], and patients with multiple diseases account for up to 78 percent of primary care consultations [8]. Eliminating these age-related diseases is essential for ensuring a healthier and more capable society moving forward.

Line graph showing projections of millions of persons with Alzheimer's disease from 2010 to 2050, with separate lines for total, age 85+, age 75-84, and age 65-74. Total cases increase from about 5 million in 2010 to around 14 million in 2050, and the 85+ group rises most steeply.
Figure 1. Projections of the number of people who will suffer from Alzheimer’s disease dementia in the United States by 2050. Over half of Alzheimer’s disease dementia sufferers in 2050 will be aged 85 years or older. Figure adapted from Hebert et al. 2013 [6].

Disease-focused initiatives have shown that though biology is complicated, concerted human effort does allow us to influence how it affects us. For example, the decades-long national push to advance cancer research, which has stretched from the National Cancer Act (1971) to the Cancer Moonshot (2016), has raised five-year cancer survival from 49 percent in the mid-1970s to 70 percent today [9].

While such improvements are certainly meaningful, even focused initiatives to tackle specific diseases take time to impact the population (Figure 2). Further, multimorbidity—the presence of multiple diseases or conditions—is so prevalent at advanced age that curing a common disease like cancer would not dramatically reduce the population’s overall disease burden: eliminating all cancer deaths would add only about three years to U.S. life expectancy at birth [10]. We intuitively know, and can observe from the incidence of major diseases with age (Figure 3), that young people don’t typically get heart attacks, dementia, or cancer, while older people get them all—and often more than one at a time. The prevalence and non-random clustering of multimorbidity in older people suggest that the risks of age-related diseases are not independent [11]. This interdependence of age-related diseases could be due to one or more shared drivers of disease. As such, tackling disease targets on a “one-by-one” basis may not be an optimal strategy for significantly addressing the growing healthcare burden within the next few decades.

Line graph of United States cancer deaths per 100,000 standard population from 1999 to 2019 for males and females. Both decline steadily, with males consistently higher than females.
Figure 2. Age-adjusted United States cancer death rates decreased by 27 percent between 1999 and 2019. Figure recreated using data from the Centers for Disease Control and Prevention [12].
Line graph showing the incidence of cancer, cardiovascular disease, dementia and diabetes by age. Cancer and cardiovascular disease rise sharply after age 60, dementia rises sharply after age 80, and diabetes rises gradually from middle age before levelling off.
Figure 3. The incidence of major diseases and symptoms such as cancer, cardiovascular disease, Alzheimer’s disease dementia and diabetes increases with age, often dramatically. Data aggregated from the Agency for Healthcare Research and Quality (2014), the American Heart Association (2015), the Alzheimer’s Association (2017), and the International Diabetes Federation (2013) [13–15].

The MCARD strategy

The MCARD strategy envisions an alternative approach to identifying therapeutics: mobilizing every United States clinical trial to find therapies that are effective against multiple age-related diseases. Semaglutide, a GLP-1 drug first approved for type 2 diabetes in 2017, is one such therapy: separate large trials have since found that it reduces heart attacks, strokes and cardiovascular deaths [16], slows chronic kidney disease [17], and treats fatty liver disease [18], with each benefit confirmed years after its first approval.

Achieving this goal will involve including in every clinical trial non-invasive biomarkers that measure a given drug’s effects on the biological mechanisms coupling the occurrence of multiple age-related diseases. We call these biomarkers “mechanistic” biomarkers: they measure the biology driving disease, rather than biology that is caused by or correlated with disease. (High) blood pressure and (high) cholesterol are examples of successful mechanistic biomarkers: blood pressure predicts the incidence of multiple cardiovascular diseases, kidney failure, and retinal disease [19–21], and cholesterol predicts ischemic heart disease [22]. Because these biomarkers measure the biology that drives disease outcomes, they have evolved into surrogate endpoints [23]: changing the biomarkers demonstrably affects disease outcomes [24, 25].

The same path remains open for new biomarkers: in 2025, the FDA qualified change in hip bone mineral density as a surrogate endpoint for fractures in osteoporosis drug trials, based on data from more than 160,000 participants in 52 past clinical trials [26]. This was possible because bone mineral density had been measured alongside fractures in dozens of trials.

The past two decades of geroscience research have demonstrated that we can target with interventions the biological mechanisms that drive aging [27, 28]. These mechanisms, which include clonal hematopoiesis (the age-related expansion of mutated blood stem cells) [29], chronic inflammation, immune system weakening, declining mitochondrial function, and loss of muscle, among other things, are promising leads for mechanistic biomarker development.

Because the number of such biological mechanisms is much smaller than the number of diseases that could afflict an individual, researchers could measure a drug’s impact on each mechanism using small fluid samples collected during existing clinical trials, thus eliminating the need to measure clinical endpoints for every possible disease. Blood proteomics can already measure thousands of proteins in a single small sample, and in more than 50,000 UK Biobank participants, over 650 of these proteins were each associated with at least 50 diseases [30].

Aims

In summary, MCARD proposes to address the impending epidemic of age-related multimorbidity in the United States and worldwide via a novel approach to clinical trials: by mobilizing every clinical trial to evaluate a therapy’s potential to treat multiple diseases at once, and doing so by measuring during every clinical trial a set of biological mechanisms that couple multiple age-related diseases. To enable this outcome, MCARD aims to:

  1. Facilitate the coalitions necessary for developing clinical-grade, minimally invasive biomarkers for interpretable mechanisms of age-related decline;
  2. Spearhead the initial clinical trials to validate these mechanistic biomarkers as surrogate endpoints; and
  3. Orchestrate the necessary institutional infrastructure and political mandate to accomplish MCARD’s core goal.

References

  1. U.S. Census Bureau (2023). U.S. population projected to begin declining in second half of century [2023 National Population Projections, press release]. https://www.census.gov/newsroom/press-releases/2023/population-projections.html
  2. United Nations, Department of Economic and Social Affairs, Population Division (2022). World Population Prospects 2022: Summary of Results. UN DESA/POP/2022/TR/NO. 3. https://www.un.org/development/desa/pd/sites/www.un.org.development.desa.pd/files/wpp2022_summary_of_results.pdf
  3. Niccoli, T., & Partridge, L. (2012). Ageing as a risk factor for disease. Current Biology, 22(17), R741–R752. https://doi.org/10.1016/j.cub.2012.07.024
  4. Levin, A. T., Hanage, W. P., Owusu-Boaitey, N., Cochran, K. B., Walsh, S. P., & Meyerowitz-Katz, G. (2020). Assessing the age specificity of infection fatality rates for COVID-19: systematic review, meta-analysis, and public policy implications. European Journal of Epidemiology, 35(12), 1123–1138. https://doi.org/10.1007/s10654-020-00698-1
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  7. Centers for Medicare & Medicaid Services (2012). Chronic Conditions among Medicare Beneficiaries, Chartbook, 2012 Edition. Baltimore, MD. https://www.cms.gov/research-statistics-data-and-systems/statistics-trends-and-reports/chronic-conditions/downloads/2012chartbook.pdf
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  14. Alzheimer’s Association (2017). 2017 Alzheimer’s disease facts and figures. Alzheimer’s & Dementia, 13(4), 325–373. https://doi.org/10.1016/j.jalz.2017.02.001
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  17. Perkovic, V., Tuttle, K. R., Rossing, P., et al. (2024). Effects of semaglutide on chronic kidney disease in patients with type 2 diabetes. New England Journal of Medicine, 391(2), 109–121. https://doi.org/10.1056/NEJMoa2403347
  18. Sanyal, A. J., Newsome, P. N., Kliers, I., et al. (2025). Phase 3 trial of semaglutide in metabolic dysfunction–associated steatohepatitis. New England Journal of Medicine, 392(21), 2089–2099. https://doi.org/10.1056/NEJMoa2413258
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