As I highlighted in my previous blog, A Look at Human Longevity & Life Expectancy, our global population is experiencing a significant and rapid increase in its aging demographic. For instance, Germany is projected to have nearly one-third of its adult population in the over 65 years category by 2035. We understand that aging is often associated with the onset of multiple chronic diseases. The presence of these conditions can significantly impact the quality of life in older age and simultaneously place a substantial burden on the healthcare systems. This trend necessitates a fundamental reevaluation of our current medical approaches.

The Nationale Akademie der Wissenschaften Leopoldina in Germany has just released a new report, The Leopoldina Discussion: Health-Extending Medicine in an Aging Society. This report proposes a paradigm shift in how we approach healthcare when it comes to aging. Instead of solely focusing on treating aging-related diseases, it advocates for preventing or mitigating biological aging itself. The report provides a clear roadmap, emphasizing key areas such as investing in science of aging, integrating prevention into clinical workflows, aligning policy structures, and fostering cross-sector collaboration.

If adopted, this approach could significantly shift medicine toward extending not just lifespan, but also years of robust, independent life.

Intervene at the level of the biological mechanisms of aging, rather than waiting for age-related diseases to manifest. The aim should be to delay or even prevent multiple chronic conditions simultaneously.

I’ve been reviewing the Leopoldina Report, and I consider it to be an excellent example of how a nation and society can care for its older generation while also managing healthcare costs. The Leopoldina report’s focus on extending a healthy lifespan by preventing age-related diseases through addressing the underlying biological aging process is particularly compelling.

What I find extremely attractive about this approach is the idea of redefining aging as a clinical target. This involves pivoting funding and strategies, encouraging collaborative infrastructures, and reforming healthcare systems for longevity. This matters because instead of managing each disease separately, the goal is to find single, minimal interventions that could lower risk across multiple domains.

The report’s pivoted strategy from reactive to proactive and preventive care includes:

Redefine our Thinking and Medical Process when it Comes to Aging

A fundamental shift in perspective is required to effectively combat aging and extend healthy lifespans. Aging should not be considered an unavoidable process but rather a clinical target for intervention. This necessitates prioritizing funding and strategic efforts toward preventive measures and early interventions based on the biology of aging. It is crucial to foster a collaborative infrastructure environment among research networks and clinical programs by promoting new trial designs, biomarker discovery, and cross-disciplinary approaches. Finally, healthcare systems themselves must be reformed to align with longevity-focused strategies. This will ensure that insurance, guidelines, and workforce training support the goal of extending “health span” and mitigating chronic diseases.

The Foundation of Report’s Core Idea

• Aging is not just a risk factor but a common driver of multiple diseases, like cardiovascular disease, cancer, diabetes, and neurodegeneration.
• The mechanisms of aging (e.g., cellular senescence, telomere attrition, mitochondrial dysfunction, loss of proteostasis, epigenetic alterations, inflammation) are shared across many diseases.
• By addressing these upstream processes, one could theoretically delay the onset or reduce the severity of several diseases at once—“multi-disease prevention”.

The Proposed Interventions Target the Mechanistic Level of Aging

The report suggests to work towards interventions at the level of mechanisms of aging, specifically through mechanism-based target discovery, which could protect from chronic diseases.

The report explores various therapeutics and metabolic aspects that have shown promise in addressing the underlying mechanisms of chronic diseases or should be targeted for drug discovery. A key takeaway is the potential for a single intervention to reduce risk across multiple areas. While not a new concept, the report emphasizes the critical importance of timing, suggesting that intervention before disease onset offers the best chance to preserve function and prevent cascading decline, a principle that should also be applied to the concept of aging itself.

“The study of biology of aging is bound to yield new targets for geroprotectors.”

To identify new targets for geroprotectors, it is essential to first understand how maintenance and repair mechanisms and the cellular stress response operate within the context of an aging organism. Since only achievable in the context of a living organism, observational studies in a range of animal models have to be implemented.

While the report suggests an approach that should combine mechanistic investigations into the biology of aging with systems approaches to understand how a specific mechanism affects complex signaling networks in cells and tissues, in my humble opinion, it is not taking the whole humanity of the patient into account. What I mean by that: recent research has shown that one’s mental state, or in other words the degree of happiness and being content/ having a role/function late in life greatly contributes to the health of older adults (e.g., via reduced stress, lower levels of inflammation / systemic inflammation).

It is also important to consider the effects of sex, in utero conditioning, exposure to psychosocial stress, nutritional stress, and environmental exposures, as these are emerging as critical determinants of human aging trajectories and susceptibility to disease (Argentieri et al., 2025). These factors have complex effects on the mechanisms of aging and are often challenging to model in a laboratory setting.

Basic research on the mechanisms of aging has already provided therapeutic concepts for delaying chronic age-related diseases.

Integration of Data from the Whole Organism

Aging is a complex and interconnected process that impacts all physiological functions. Therefore, a systems-level approach integrating diverse data is essential to understand it comprehensively. A robust “systems aging infrastructure” is needed to integrate various data types from model organisms and humans, including electronic health records. The NIH-funded Cellular Senescence Network (SenNet) which creates an atlas of senescent cells in human and mouse organs by integrating researchers and leveraging existing expertise across different research centers, serves as an excellent model for such a network, and enhances our understanding of the translatability of findings in preclinical species/animal models to humans.

Combining this systems aging approach with mechanistic studies will offer new insights for developing effective geroprotective treatments, contributing to the medicine of the future for a healthy aging society. It is particularly timely to investigate how the geroprotective effects of metabolic drugs (e.g., GLP-1R agonists, SGLT2 inhibitors) impact aging mechanisms. To advance this research, new tools are needed to measure metabolism, genome stability, and repair capacity at the single-cell level.

Targeting Mechanisms of Aging

We’ve seen a remarkable doubling of life expectancy over the past 150 years, a change that’s occurred without any alteration to the human genetic makeup. This clearly indicates that non-genetic factors have played a significant role in extending both lifespan and health span. The widespread multimorbidity in individuals over 65 likely stems from the progressive and cumulative impact of biological aging mechanisms, which in turn reduces resilience. The presence of chronic diseases, often multiple, is commonly observed after 65 and contributes to the decline in healthy lifespan. Ultimately, the goal is not merely to prolong life, but to extend a healthy and vibrant life.

Targeting mechanisms of aging is suggested with a multitude of different drugs, as listed in the report. I wanted to dive a little deeper on those various types of therapeutics, highlighting some key facts. Though, it should be noted, that I did not balance the listed therapeutic findings with their potential side effects or concerns. Some of these therapies include:

1. Senotherapeutic drugs: These drugs selectively target and remove (e.g., senolytics) senescent cells, which are a hallmark of aging. Their benefits include reducing chronic inflammation and tissue dysfunction, both of which contribute to age-associated diseases including cancer (Campisi, 2012).
   1. Senotherapeutics have been shown to extend the median lifespan in mice and are currently being investigated in clinical trials.
   2. Senotherapeutic trials are largely designed around specific age-associated diseases such as Alzheimer’s disease (Gonzales et al., 2023).
2. mTOR inhibitors (e.g., rapamycin): These drugs inhibit the mTOR pathway, a key regulator of cell growth, metabolism, and nutrient sensing. By inhibiting mTOR, rapamycin can reduce the rate of aging, improve metabolic function, and alleviate age-related disease (Harrison et al., 2009).
   1. Rapamycin is considered a therapeutic approach that mimics caloric restriction (CR).
3. GLP-1R agonists and SGL2 inhibitors: Initially developed to treat type 2 diabetes mellitus, these drugs are now applied to treat weight loss, obesity, heart failure, and kidney disease (Deanfield et al., 2024; Colhoun et al., 2024; Heerspink et al., 2020).
   1. GLP-1R agonists mimic the effects of the hormone GLP-1, which stimulates insulin release, suppresses glucagon secretion, slows gastric emptying, and can reduce appetite. This leads to improved glycemic control, reduced cardiovascular risk (including reduced risk of stroke), potential neuroprotective effects, and a reduced risk of end-stage renal disease. These effects may help with age-related cognitive decline, neurodegenerative diseases, and potentially reduce cellular aging
   2. SGL2 inhibitors block the reabsorption of glucose in the kidneys, resulting in increased glucose excretion in the urine and lower blood glucose levels. This leads to improved glycemic control, cardiovascular risk reduction (particularly reduced risk of heart failure), renoprotective effects (slowing the progression of kidney disease), and potential anti-inflammatory and antioxidant effects. These benefits may help with age-related conditions like heart failure, chronic kidney disease, and potentially reduce the risk of certain cancers and infections. 
4. DREAM complex: In C. elegans, the DREAM complex was shown to be a master regulator of cellular DNA repair capabilities, targeting genome instability. Specifically, the DREAM complex represses DNA repair gene expression in somatic tissues, thereby curbing their repair capacity and consequently limiting developmental growth, organismal health, and lifespan upon DNA damage (Bujarrabal et al., 2023).
   • Again, I did not balance out the potential side effects or concerns (e.g., increased risk for cancer, potentially at play here)
5. Yamanaka factors (OSKM): Named after Dr. Shinya Yamanaka, who received the Nobel Prize for his discovery, these are a set of transcription factors (e.g., Oct4, Sox2, Klf4, and c-Myc) that can reprogram somatic cells into pluripotent stem cells (Liu et al., 2028).
   1. Partial cellular reprogramming offers a potential approach for regenerating tissues from one’s own cells, even in older adults.
   2. Mounting evidence indicates that partial reprogramming through the Yamanaka factors resets the biological age of cells.
   3. Reprogramming technologies have already entered clinical trials, for instance, to replace dopaminergic neurons in Parkinson’s disease patients (Bose et al., 2022).
6. Anti-inflammatory therapies: These therapies target chronic low-grade inflammation, often referred to as “inflammaging,” which underlies many age-related diseases (see also the senotherapeutic drugs summary above).
7. Caloric restriction (CR) mimetics: These agents pharmacologically induce effects similar to caloric restriction, which is known to extend lifespan and delay disease in animal models. It is thought that CR elicits some of its effects by increasing resilience (see mTOR summary above).
8. Mitochondrial protectants: These agents stabilize mitochondrial function, which deteriorates with age and is linked to multiple diseases.

The report suggests to enhance this mechanism-based target discovery approach by integrating multi-omics and systems biology approaches with AI/ML integration in drug discovery. It is further suggested to test these geroprotective therapeutics with stratified and adaptive clinical trials.

Concluding Notes

This new Leopoldina report advocates for a significant shift in our approach to healthcare, moving from merely treating age-related diseases to proactively preventing biological aging itself. This forward-thinking strategy is a direct response to the global demographic trend of aging populations, as age-related risks place increasing pressure on healthcare systems and necessitate a fundamental reevaluation of our current medical practices.

The report clearly outlines a path forward: prioritizing investment in science of aging, integrating prevention into clinical workflows, aligning policy structures, and fostering cross-sector collaboration. Adopting these recommendations would transform medicine, extending not only lifespan but also the years individuals can enjoy robust, independent lives.

As the Academy emphasizes, the goal is “Instead of treating age-related diseases after they occur, preventing them by addressing underlying biological aging processes with the aim to extend healthy lifespan”

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