ABSTRACT

This project investigates the role of protein prenylation—a post-translational modification mediated by isoprenoid metabolites—in the aging immune system. Aging is associated with chronic inflammation (“inflammaging”), yet the underlying molecular mechanisms remain poorly understood. Preliminary data suggest that aging leads to a decline in isoprenoid metabolism, impairing protein prenylation and contributing to immune dysfunction. The study hypothesizes that this decline can be reversed through dietary supplementation with isoprenoids. Using mouse models, the research will characterize age-related changes in protein prenylation and evaluate the effects of isoprenoid supplementation on metabolic and immune parameters.

Lay Summary:

As the population of older adults continues to grow, there is a critical need to understand the factors driving health complications in aging and develop strategies that can enhance quality of life in the elderly. Improving immune function in older age has the potential to reduce heightened risks of infectious diseases, diminished vaccine effectiveness, inflammation, and other health challenges associated with suboptimal immune responses. However, the molecular and cellular mechanisms underlying immune decline in aging remain incompletely understood, limiting the development of targeted therapeutic interventions.

This study identifies protein prenylation—a post-translational modification that regulates immune signaling—as a potential molecular mechanism influencing immune fitness in human aging. The research aims to map protein prenylation status during aging and evaluate the effects of a prenylation-targeted therapeutic strategy on metabolic and immune fitness. Specifically, it will assess whether dietary supplementation with isoprenoids (precursors to prenylation) can reverse age-associated immune decline. If successful, this research could lead to non-invasive interventions that rejuvenate immune function and improve health outcomes in aging populations.

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ABSTRACT

This study investigates the mechanisms behind ketogenic diet-induced hypercholesterolemia (KDHC) in lean adults. It tests whether elevated LDL-c results from increased synthesis or absorption. Using deuterated water and serum markers, the project compares cholesterol metabolism in KDHC responders and non-responders. Findings will inform safer KD implementation and cardiovascular risk management.

Lay Summary:

Cholesterol plaque in the arteries is a leading cause of heart disease and death worldwide. Very high cholesterol levels cause plaque and heart disease early in life and are often due to genetic differences. However, genetic differences are not the only possible cause of very high cholesterol levels. A ketogenic diet can also cause very high cholesterol levels. This is problematic because very high cholesterol levels increase the risk of heart disease. Not everybody is susceptible to the cholesterol-raising effect of ketogenic diets. The cholesterol-raising effect happens more often in healthy, lean adults. The reason it happens is not known.

Our research aims to understand why a ketogenic diet can raise cholesterol so much and why some people are susceptible to this problem. Understanding this process could help treat people who have this condition and could help us understand which people might tolerate ketogenic diet therapies used for other diseases. It could also teach us fundamental new things about how cholesterol metabolism works in people. Cholesterol travels through the bloodstream in particles called lipoproteins. Some of the cholesterol in these lipoproteins is produced in the liver. The other main source of cholesterol in lipoproteins is the food we eat, because animal products contain cholesterol and our gut absorbs some of it. For this reason, we will study how cholesterol is produced and absorbed in the body. Our goal is to learn how cholesterol production and absorption are affected in people who have very high cholesterol because of a ketogenic diet.

One possibility is that a ketogenic diet causes too much cholesterol to be made in the liver. This is plausible because the liver can convert the ketones made on a ketogenic diet to cholesterol molecules. Another possibility is that the people who are susceptible to high cholesterol on a ketogenic diet absorb more cholesterol from the diet than the typical person. We will study healthy adults with a normal weight to explore these options because they are more likely to have high cholesterol on a ketogenic diet. We will measure cholesterol absorption in all participants and compare absorption in “Responders” who experience high cholesterol on the ketogenic diet to “Nonresponders” who do not. If high cholesterol production is the cause of high blood cholesterol on a ketogenic diet, we expect to see higher cholesterol production in these Responders during the ketogenic diet period than during the normal diet period. By learning how the ketogenic diet causes high cholesterol, doctors and patients can have better discussions about diet and heart health. This research could help improve dietary guidelines to treat high cholesterol and prevent heart disease. Finally, this research will help us learn how cholesterol metabolism responds to changes in the diet.

The post Impact of the Ketogenic Diet on Cholesterol Synthesis and Cholesterol Absorption appeared first on Longer Life Foundation.

ABSTRACT

Using the SPAN dataset, this project applies transformer-based survival models and large language models to predict mortality. It integrates structured data (e.g., biomarkers, personality) and transcribed life narratives to identify predictive features. The approach emphasizes scalable, non-invasive predictors and aims to improve risk stratification. Future directions include biomarker expansion and R01 submission.

Lay Summary:
Accurately predicting individual differences in mortality risk remains a critical public health challenge. Accurately predicting individual differences in mortality risk remains a critical public health challenge. As the global population ages, identifying reliable predictors of mortality can help target interventions, inform personalized care strategies, and enhance quality of life in later years. For over 17 years, the St. Louis Personality and Aging Network (SPAN) has collected a wide variety of person-level (e.g., interviews, personality measures, blood-based biomarkers) and environmental-level (e.g., geocoding) variables.

This project uses this richly phenotyped longitudinal dataset to develop predictive models that integrate biological, psychosocial, and environmental factors to assess mortality risk. It applies state-of-the-art transformer models—advanced AI tools—to analyze both traditional variables and transcribed life narratives. By combining structured data with language-based insights, the study aims to uncover new risk signals and improve the accuracy of mortality prediction. Ultimately, this research could lead to more effective prevention and care strategies for older adults, especially those underserved by traditional healthcare systems.

The post AI-Driven Mortality Prediction: Integrating Biological, Psychosocial, and Linguistic Predictors of Mortality Using Deep Learning Transformer Models appeared first on Longer Life Foundation.

ABSTRACT

This study validates voluntary motor commands (VMCs) at the spinal motoneuron level as a biomarker for MS progression. Using HDsEMG and motor unit decomposition, the project tracks VMC changes over time and correlates them with clinical outcomes. Preliminary data show strong associations with strength and walk speed. The biomarker could enable earlier detection and personalized neuroplasticity therapies. NIH and DoD funding applications are planned.

Lay Summary: 
Multiple Sclerosis (MS) is a common, progressive neurodegenerative disease that affects nearly all major bodily systems and is the leading non-traumatic disabling neurological condition in young adults. While relapses in MS are easily detectable and treatable with disease-modifying drugs, the gradual progression of symptoms is harder to identify and monitor. This progression leads to accumulating disability and is often diagnosed only after irreversible damage has occurred.

This proposal introduces a novel approach to detect and monitor MS progression using voluntary motor commands (VMC) at the level of spinal motoneurons. By decoding nerve signals transmitted to muscles, researchers can assess how the central nervous system controls movement. Preliminary data suggest that changes in VMC parameters over time are greater in patients with progressing MS than in those with stable MS. The study will continue longitudinal assessments to validate VMC as a sensitive biomarker for disease progression. If successful, this method could enable earlier intervention, improve treatment decisions, and support personalized rehabilitation strategies to prevent disability in MS

The post A Novel Neurophysiological Biomarker for MS Disease Progression appeared first on Longer Life Foundation.

ABSTRACT

This project introduces ReCAP, a host-independent protein degradation platform using bacterial AAA+ proteases to target undruggable proteins like KRAS and c-MYC. Through directed evolution and antibody-adaptor chimeras, ReCAP enables selective degradation in mammalian cells. It addresses limitations of current degradation technologies and offers a modular, programmable strategy for precision oncology. The work spans six years of investigation and includes plans for NIH and DARPA funding and SBIR/STTR commercialization.

Lay Summary: 
Many cancers are driven by abnormal proteins called oncoproteins, which help tumor cells grow and spread. These proteins are often “undruggable” because they lack suitable binding sites or quickly develop resistance to existing treatments. This project proposes a new strategy: instead of blocking oncoproteins, it aims to destroy them using a programmable system derived from bacterial protein machines.

The system, called ReCAP (Reprogrammed ClpX for Antigen-specific Proteolysis), is based on ClpXP—a bacterial protease that can shred unwanted proteins. The project will reprogram ClpXP to target specific oncoproteins like KRAS and MYC using two methods: (1) engineering ClpX to recognize these proteins directly, and (2) attaching antibody fragments to ClpX via adaptors that guide the target proteins to the system. This dual targeting approach enhances precision and flexibility. The system will be tested in human cells to ensure it selectively eliminates cancer-causing proteins without harming normal ones. If successful, ReCAP could become a powerful tool for personalized cancer therapy and may be adapted to treat other diseases caused by harmful proteins.

The post Reprogramming AAA Proteases for Personalized Cancer Immunotherapy appeared first on Longer Life Foundation.

ABSTRACT

Across a lifetime, neurons must retain a remarkable level of plasticity that facilitates learning, memory, and behavior. As animals encounter new sensory stimuli and learn complex behaviors, these experiences trigger changes in the activation of the state of neurons in the brain. In turn, increased neuronal activity induces the transcription of thousands of genes, the products of which dynamically modify the cells and circuits of the brain. Neuronal activity-induced transcription is, however, a costly and risky endeavor. During transcription, the DNA is cut, unwound, and eventually resealed in a process that has the potential to create permanent mutations. How then do animals balance the benefits of elevated neuronal activity for plasticity with the risks it poses to the stability of their genetic code? The goal of this proposal is to identify the molecular mechanisms that protect neuronal genomes from damage during periods of heightened neuronal activity. In our first aim, we will identify new mechanisms that repair activity-induced DNA damage, with an eye towards future work assessing how these protective mechanisms change with age in mouse models. In our second aim, we will identify the burden of mutations that accrue during aging at activity-induced genes in different types of brain cells. These studies will identify the cell types most susceptible to damage and will highlight gene candidates with high levels of mutations that may contribute to age-associated cognitive decline. Together, our work will provide foundational knowledge of how diverse neuronal cell types maintain transcriptional control and genome stability with age and how these genome control mechanisms go awry in aging and degenerative disease.

Lay Summary: 
Our aging population is expected to develop increased incidences of neurodegenerative disease and dementia, but the molecular mechanisms that underlie these complex processes remain poorly understood. This proposal aims to understand how neuronal activity-dependent gene expression and DNA damage repair can regulate brain aging by leveraging a newly identified, activity-inducible protein complex, NPAS4:NuA4. Our work will shed light on how changing levels of activity in the brain influence the accumulation of DNA damage across neuronal genomes as we age and the consequences of this damage for brain function. These experiments will lay critical groundwork for designing targeted strategies to slow or reverse decline in the neuronal cell types most susceptible to
age-dependent diseases.

The post Neuronal Activity-Dependent DNA Repair in Healthy Aging appeared first on Longer Life Foundation.

FINAL REPORT

Chemotherapy remains one of the most effective treatments for cancer, yet its benefits are frequently accompanied by systemic toxicities that extend beyond tumor tissue. Among these, skeletal and cardiac muscle loss are increasingly recognized as major determinants of morbidity, treatment intolerance, and long-term functional decline. Anthracyclines such as doxorubicin are well known to cause cardiotoxicity, but they also induce a broader catabolic state characterized by muscle atrophy, altered substrate utilization, and impaired regenerative capacity. These effects are particularly consequential in older individuals, in whom baseline muscle mass and metabolic flexibility are already diminished.

Muscle loss during cancer therapy intersects biologically with aging. Both processes involve dysregulated nutrient sensing, mitochondrial stress, inflammatory signaling, and impaired proteostasis. As lifespan increases and more patients survive cancer into older age, preventing therapy-induced muscle decline has become central not only to oncology outcomes but also to long-term healthspan. Interventions that modulate metabolism, such as fasting, macronutrient manipulation, or pharmacologic targeting of nutrient-sensing pathways, are increasingly promoted to mitigate chemotherapy toxicity, yet their effects on cardiac and skeletal muscle remain incompletely defined.

In this context, our project examined whether dietary interventions could modify doxorubicin-induced muscle atrophy and cardiac remodeling. We found that intermittent fasting induced marked adipose tissue remodeling that unexpectedly accelerated cardiac wasting in the setting of doxorubicin exposure. Rather than protecting against chemotherapy-associated muscle loss, fasting altered systemic metabolic signaling, thereby amplifying cardiomyocyte atrophy. In contrast, a high-fat diet prevented doxorubicin-induced cardiac muscle atrophy and preserved cardiomyocyte size under stress conditions. Mechanistic studies identified lysosomal lipolysis as a critical regulator of cardiomyocyte growth and survival, a pathway not previously recognized as central to chemotherapy-associated cardiac wasting. Unexpectedly, high protein feeding failed to rescue cardiac muscle mass and, in some settings, exacerbated atrophy, refining prevailing assumptions regarding protein supplementation during catabolic stress.

Although the original proposal focused on chemotherapy-associated muscle loss, this line of investigation ultimately led to the downstream identification of a novel therapeutic strategy that prevents muscle loss in the broader context of weight reduction. This discovery extends beyond anthracycline cardiotoxicity and has potential implications for aging-associated sarcopenia, obesity treatment, and intentional weight loss. Further translational development and grant submissions are in progress. Specific molecular components and therapeutic details are withheld pending intellectual property protection and considerations.

ABSTRACT 

Doxorubicin (Dox) is a commonly used chemotherapeutic agent that has adverse effects on skeletal and cardiac muscle. Dox cardiotoxicity is initially characterized by skeletal and cardiac muscle atrophy and cardiac fibrosis. Dox-induced heart and skeletal muscle toxicity can progress to contractile dysfunction, sarcopenia, heart failure, and ultimately physical frailty – a phenotype of accelerated aging – and premature mortality. The immediate goal of this proposal is to determine how a range of dietary interventions can mitigate Dox toxicity and in so doing to identify biological mechanisms that can be therapeutically exploited. By understanding the mechanisms of accelerated aging and frailty, we can identify ways of intervening to mitigate the process. Accomplishing this objective will help us understand how to prevent physical frailty long-term. As an example, in a series of experiments published recently in Cell Metabolism, my laboratory discovered that sustained alternate-day fasting (ADF) in mice provokes Dox cardiotoxicity. In new studies in the first year of our Longer Life Foundation Program Award, we identified that Dox combined with ADF leads to the expansion of brown adipose tissue and increases in a secreted axonal guidance protein, SLIT2. By leveraging human samples from the Penn Heart Failure Study and aptamer proteomics, we identified that SLIT2 is the top biomarker that distinguishes Dox cardiomyopathy from other cardiomyopathies, and we have now further shown that SLIT2 is necessary and sufficient for Dox cardiotoxicity. This work, which was one specific aim of our proposal, is presently under consideration at Cell.

Having exploited our observation that fasting potentiates Dox toxicity to identify a novel biomarker and therapeutic (SLIT2), we currently propose to identify a dietary regimen that can mitigate Dox toxicity. In new preliminary studies, we randomized mice to standard high carbohydrate chow or a high protein, or high-fat diet. In these studies, we find that a high-fat diet mitigates Dox cardiotoxicity while a high-protein diet exacerbates it. These findings are surprising because a high-protein diet is currently considered the standard dietary approach to prevent muscle loss, albeit with limited scientific evidence for efficacy. Dox-treated mice fed a high-protein diet also exhibited reduced exercise capacity compared with Dox-treated mice fed a high-fat diet. In an analogous manner to what we have accomplished with fasting – namely, we used our fasting model to identify a translational disease mechanism and biomarker – we now propose to a) identify how high-fat feeding attenuates Dox cardiotoxicity, b) identify mechanisms of cardiac muscle toxicity induced by high protein intake, and c) evaluate the effect of a high protein diet on skeletal muscle mass and contractile function in Dox-treated mice.

LAY SUMMARY 

Chemotherapy is a common treatment for cancer, but it can worsen other age-related health problems, such as heart disease, muscle loss, and weakness. In the first year of our Longer Life Foundation Award, we showed that intermittent fasting increases the side effects of chemotherapy in mice. This research has helped us identify potential new treatments to reduce these side effects. In the second and third years, we will study if other dietary approaches, like high-protein or high-fat diets, can change the side effects of chemotherapy. We will also explore new methods to help manage and reduce these side effects. These studies have enormous potential relevance not only to humans receiving chemotherapy but also to the selection of dietary macronutrients during aging and muscle loss.

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ABSTRACT

Non-communicable diseases (NCDs) are the primary cause of death and disability globally, accounting for 71% of the 41 million deaths annually. Among NCDs, hypertension (HTN) is a significant challenge in the United States, disproportionately affecting older, low-income, and minority communities. In St. Louis, HTN prevalence increased from 23% in 2007 to 36% in 2016, with a higher incidence in Black populations (44%) compared to white populations (31%).

In response, the US Surgeon General called for research on the impact of social determinants of health (SDOH)—the social and environmental conditions that affect health and well-being—on HTN development and management. Frameworks such as Healthy People 2023 emphasize healthcare accessibility and neighborhood and built environment factors as key health domains. However, these factors are often studied in isolation, highlighting the need for tools to comprehensively assess the multiple SDOH influencing HTN. To address this need, this project aims to establish a geospatial model to assess social and environmental risk factors associated with NCDs, focusing on HTN in Greater St. Louis. The model will merge objective and perceived data from two domains: healthcare accessibility and neighborhood and built environment. This will elucidate the complex associations between HTN and SDOH factors, serving as a scalable model for other health issues. The project will be guided by two concurrent aims: Aim 1 is to utilize a novel geospatial SDOH model to identify geographic disparities in HTN, healthcare accessibility, and neighborhood and built
environment factors in St. Louis. This model will integrate health and demographic data from approximately 1.5 million EMR patients from the BJC Network, GIS-modeled health accessibility (e.g., travel time estimates), outdoor air pollution, noise, and light exposure data for all EMR participants, and perceived health accessibility and environmental exposure data from a subset of 300 participants. Aim 2 is to utilize the geospatial SDOH model to evaluate the association between HTN and objective and perceived healthcare accessibility and neighborhood and built environment SDOH factors. This will serve as a “proof of concept” evaluation using advanced statistical models to assess the relationship between HTN and both objective measures (e.g., proximity to diagnosis locations, pharmacy locations, and geographical neighborhood characteristics) and perceived measures of healthcare access.

Additionally, to explore the interaction between environmental exposures and healthcare accessibility. We anticipate that objective and perceived measures of SDOH will
vary geographically, representing potential disparities in health services accessibility. We also expect that participant-reported accessibility barriers (e.g., travel costs, time, availability) will vary by objective measures (e.g., distance, travel time). In the Exploratory Aim, we expect that objective and perceived measures of accessibility will be associated with HTN. Overall, results will provide novel information regarding the local geographic drivers of HTN health services accessibility across diverse populations in St. Louis, MO. This information will support the future development of interventions aiming to reduce disparities related to HTN accessibility and outcomes.

Lay Summary
This project aims to establish a geospatial model to assess social and environmental risk factors associated with hypertension (HTN) in Greater St. Louis, merging objective and perceived data on healthcare accessibility and neighborhood factors. Guided by two aims, the study will identify geographic disparities in HTN and evaluate the association between HTN and both objective and perceived SDOH factors, including the interaction between environmental exposures and healthcare accessibility. The findings will inform the development of targeted interventions to reduce disparities in HTN accessibility and outcomes across diverse populations in St. Louis.

The post Investigating Geographic Disparities in Social Determinants of Health and Hypertension in the Greater St. Louis Area appeared first on Longer Life Foundation.

FINAL REPORT

Muscle dysfunction and impaired exercise tolerance are common co-morbidities of aging. This aging-associated muscle dysfunction manifests as reduced skeletal muscle mass and a persistent decline in muscle metabolism. Loss of muscle mass and metabolic ability can have detrimental effects on patient mobility and independence, as well as increase the risk of debilitating falls, the need for long-term care, and contribute to mortality. Delaying or preventing muscle dysfunction in aging populations would improve patient quality of life and lessen disease severity. Yet, the molecular mechanisms responsible for muscle dysfunction in these populations are not completely understood — meaning that therapeutics for effectively combating and potentially even preventing muscle dysfunction are lacking.

Our lab recently identified Site-1 Protease (S1P) as a regulator of both skeletal muscle mass and mitochondrial metabolism. Furthermore, we found that in humans, S1P is linked to exercise impairment and mitochondrial dysmorphology (PMID: 31070020). Our recent report shows that deletion of S1P in skeletal muscle increases muscle mass in aged mice and that S1P suppresses muscle mitochondrial metabolism (PMID: 37002930). In year 1 of the award period, we generated data showing that S1P is a key regulator of energy production during muscle growth — suggesting a mechanism whereby mitochondrial metabolism controls muscle size. Year 2 of the award period is focused on (a) defining the mechanism(s) by which S1P regulates metabolism to control muscle size and (b) examining the pathological significance of this mechanism in age-associated muscle loss. Because decreased muscle mass and impaired mitochondrial metabolism are hallmarks of many disease states (i.e., muscular dystrophy, obesity, chronic kidney disease, etc), findings from this proposal may be applicable to several chronic and debilitating human diseases.

Lay Summary

Muscle loss and impaired muscle energy production are common co-morbidities of aging; however, the molecular mechanisms responsible for muscle loss and declines in metabolism in aging populations are not clearly understood — meaning that therapeutics for effectively combating and potentially preventing muscle dysfunction are lacking. Our lab has identified a molecular player that controls both muscle size and metabolism. During Year 1 of the Longer Life Foundation Award, we discovered that muscle size is partly controlled by muscle metabolism (manuscript in preparation). During Year 2 of the award, we will delineate the mechanism by which muscle metabolism controls muscle size and test the efficacy of targeting this mechanism to improve age-associated exercise intolerance and immobility. Completion of this work will expand the field’s knowledge of the physiology and pathophysiology of aging and our pre-clinical discoveries will be applicable to several chronic and debilitating human diseases that also result in impaired muscle mass and metabolism (i.e., cancer, muscular dystrophy, obesity, chronic kidney disease).

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ABSTRACT

Aging-related pathologies lead to an abbreviated health- and lifespan. Cellular senescence, which is an irreversible cessation of the cell cycle, occurs during aging and with associated metabolic dysfunction. The p16INK4a protein is a key regulator of the cell cycle and its activation leads to a block of the cell cycle and proliferation. While exercise exerts an anti-senescent effect, whether progressive resistance training has this effect and whether the mechanism involves p16INK4a remains undetermined. Furthermore, while targeted pharmacogenetic methods to ablate p16INK4a expressing cells improve lifespan and metabolic dysfunction, the anti-senescent effects of genetically deleting p16INK4a specifically in adipose tissue stem cells remains untested.

The work proposed in this application is based on findings that p16INK4a expression is increased in adipose and adipose tissue stem cells during aging and its associated metabolic dysfunction. To test this association, we will study whether or not an anti-senescent effect occurs with resistance exercise in concert with decreased adipose and adipose stem cell p16INK4a expression. Furthermore, we will test the effects of p16INK4a genetic deletion in adipose tissue stem cells on metabolic dysfunction across the lifespan. Overall, the findings from the proposed studies should enhance our understanding of the relationship between cellular senescence and aging-related metabolic dysfunction.

Lay Summary
Aging contributes to many pathologies including metabolic disease and the dysfunction of fat tissue. Typically, in a healthy fat pad, fat stem cells grow, proliferate and differentiate into mature fat cells. However, during aging, these fat stem cells cease to grow and proliferate, a process termed cellular senescence. Since cellular senescence is a symptom of aging, targeting senescence could be an attractive therapeutic avenue for treating the deleterious effects of aging. To this end, we will study the effects of progressive resistance exercise training and of the protein named p16INK4a on senescence in fat tissue and in fat-tissue-resident stem cells of mice. In Specific Aim 1 of this proposal, we will characterize the effects of progressive resistance training on cellular senescence and p16INK4a expression in adipose tissues and adipose tissue stem cells of wild-type mice. In Specific Aim 2, we will characterize the effects of genetically deleting p16INK4a specifically in mice’s fat stem cells over their lifespan. Overall, our proposed studies will provide novel mechanistic insight that could potentially be used to develop new countermeasures for aging and improve metabolic function and health span for the life span.

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