Mois : février 2025

Mortality among Americans aged 25-44 has risen substantially between 2011 and 2023, a new study has found, and it remains high even after having passed the COVID-related peak [1].

Riches to rags

Despite the US being one of the world’s richest countries, Americans’ average life expectancy has been lagging behind that of comparable countries by more than four years (even more when compared to top performers such as Spain and Japan). The gap has widened substantially starting at around 2010, when US life expectancy growth ground to a halt and later took an unusually hard hit during the COVID-19 pandemic (interestingly, it was followed by a robust rebound in 2022 and 2023).

Part of this multifaceted phenomenon is increased mortality in young adults. While much of it has been driven by an epidemic of illegal drugs, deaths of natural causes such as cancer have also skyrocketed. This trend worries researchers and policymakers and is being actively investigated.

Not just COVID

In a new study that originated from the University of Minnesota and Boston University and was published in JAMA Open Network, the researchers took an unusually long perspective to analyze the dynamics of excess deaths in American adults aged 25-44. The team used 2010 as their baseline and defined excess mortality as that exceeding extrapolation of 1999-2010 trends.

Having analyzed 3,392,364 deaths, they found that excess mortality per capita in this category began to rise well before the pandemic. In 2019, it was 34.6% higher than expected (i.e., had pre-2011 trends continued).

The pandemic brought another sharp increase in mortality, two major drivers being COVID-19 and drug overdoses. However, deaths from multiple other causes, including cancer, circulatory problems, and metabolic diseases, increased as well. Some of these may be connected to COVID, as studies have linked COVID infection to various complications such as cardiovascular conditions [2], or substance abuse. As a result, in 2021, all-cause excess mortality was almost three times what it had been in 2019 (116.2 vs 41.7 deaths per 100,000 population).

A complex phenomenon

Hinting at this interconnectedness is the fact that after 2021, excess mortality began to fall in several categories, such as cardiometabolic conditions. However, even for these causes, excess mortality remains much higher than pre-pandemic levels. All-cause early adult mortality was 70.0% higher in 2023 than it would have been had pre-2011 trends continued. In absolute numbers, this excess mortality translates into 71,124 deaths annually.

This might be partially due to the long-lasting effects of COVID, which are only beginning to attract researchers’ attention (“long COVID” and other complications). Another possible explanation is that drug- and alcohol-related deaths are still very high compared to a decade ago. Substance abuse is associated with multiple health hazards and might drive other causes of death.

The top five causes of death that collectively accounted for nearly three-quarters of the excess mortality in 2023 were drug poisoning (31.8% of excess mortality), the residual natural-cause category (16.0%), transport-related deaths (14.1%), alcohol-related deaths (8.5%), and homicide (8.2%). “Additionally, the combined contribution of cardiometabolic conditions, including circulatory and endocrine, metabolic, and nutritional, was substantial (9.2%),” the paper notes.

“The rise in opiate deaths has been devastating for Americans in early and middle adulthood,” said Elizabeth Wrigley-Field, lead author and an associate professor in the University of Minnesota College of Liberal Arts and Institute for Social Research and Data Innovation. “What we didn’t expect is how many different causes of death have really grown for these early adults. It’s drug and alcohol deaths, but it’s also car collisions, it’s circulatory and metabolic diseases – causes that are very different from each other. That tells us this isn’t one simple problem to fix, but something broader.”

“Our findings underscore the urgent need for comprehensive policies to address the structural factors driving worsening health among recent generations of young adults,” said author Andrew Stokes of Boston University. “Solutions may include expanding access to nutritious foods, strengthening social services and increasing regulation of industries that affect public health.”

Cancer is on the rise

While most natural causes are declining, cancer is an outlier, with excess mortality at an all-time high. A large-scale study in The Lancet last year found that cancer prevalence has increased in young compared to older cohorts, particularly in Generation Xers and millennials, for 17 out of 34 cancer types [3]. Alarmingly, cancer is often more aggressive in younger people.

This hike in cancer incidence has happened despite a declining prevalence of smoking and some other unhealthy behaviors. On the other hand, factors such as alcohol consumption, obesity, ultra-processed food consumption, and environmental pollution remain a challenge. A recent advisory from the US Surgeon General warns that alcohol is a major risk factor for cancer.

However, early detection might also have contributed to the rates of cancer in earlier cohorts. Some slow-growing cancers might be detectable now at earlier ages, affecting the statistic.

The lost Americans

Interestingly, the US was not always behind its peers in life expectancy. In 2023, a study by the University of Boston scientists aptly named “Missing Americans: Early death in the United States” stated that “The United States had lower mortality rates than peer countries in the 1930s-1950s and similar mortality in the 1960s and 1970s. Beginning in the 1980s, however, the United States began experiencing a steady increase in the number of missing Americans, reaching 622,534 in 2019 alone.” [4] The situation got much worse during the COVID-19 pandemic.

The authors of that study attributed the growing discrepancy to the lack of large-scale public health initiatives in the US. “While COVID-19 brought new attention to public health, the backlash unleashed during the pandemic has undermined trust in government and support for expansive policies to improve population health,” said the study’s lead and corresponding author Jacob Bor, associate professor of global health and epidemiology, at the time. “This could be the most harmful long-term impact of the pandemic, because expansion of public policy to support health is exactly how our peer countries have attained higher life expectancy and better health outcomes.”

Literature

[1] Wrigley-Field, E., Raquib, R. V., Berry, K. M., Morris, K. J., & Stokes, A. C. (2025). Mortality Trends Among Early Adults in the United States, 1999-2023. JAMA Network Open, 8(1), e2457538-e2457538.

[2] Lee, C. C., Ali, K., Connell, D., Mordi, I. R., George, J., Lang, E. M., & Lang, C. C. (2021). COVID-19-associated cardiovascular complications. Diseases, 9(3), 47.

[3] Sung, H., Jiang, C., Bandi, P., Minihan, A., Fidler-Benaoudia, M., Islami, F., … & Jemal, A. (2024). Differences in cancer rates among adults born between 1920 and 1990 in the USA: an analysis of population-based cancer registry data. The Lancet Public Health, 9(8), e583-e593.Chicago

[4] Bor, J., Stokes, A. C., Raifman, J., Venkataramani, A., Bassett, M. T., Himmelstein, D., & Woolhandler, S. (2023). Missing Americans: early death in the United States—1933–2021. PNAS nexus, 2(6), pgad173.

In the Journal of Nanobiotechnology, researchers have described a new method of delivering a long-lasting treatment into cartilage.

A protein that promotes autophagy

Previous work has linked expression of the FGF18 protein with healthy cartilage and joints [1]. Problems with the gene responsible for FGF18 lead to osteoarthritis [2], and it has been found to be important alongside arthritis therapies, such as hydrogels that form a lattice for cartilage growth [3]. This is because FGF18 is known to have positive effects on the FOXO3 pathway, which stimulates autophagy, the cellular self-consumption process that removes unwanted and harmful components [4].

However, using a protein as a cartilage treatment has its own problems. Recombinant proteins directly delivered into tissue don’t last very long [5], and even mRNA-based therapies are vulnerable to rapid degradation in the human body [6]. To combat this, the researchers have chosen lipid nanoparticles (LNPs), which encapsulate the mRNA in order to deliver it into cells [7].

The researchers first confirmed the existence of a link between FGF18 and osteoarthritis. A broad gene expression database has reported that elderly people have only a quarter the FGF18 of young people. Tissue samples have revealed that people who undergo total knee arthroplasty have their FGF18 reduced by half. Similarly, mice that have had arthritis artificially induced by meniscus destabilization, as well as naturally aged mice, have approximately half the FGF-18-positive cells of healthy young mice.

Exposing cartilage-generating cells (chondrocytes) to an inflammatory environment characterized by TNF-α resulted in FGF18 expression being reduced to a fourth of its normal value. Driving chondrocytes senescent by exposing them to hydrogen peroxide reduced FGF18 to two-fifths of its normal value.

Effective delivery and therapeutic effects

The mRNA delivery appeared to be effective. A cellular examination showed no toxicity to chondrocytes even at high concentrations. Unlike recombinant FGF18, the LNP-encapsulated mRNA nanoparticles penetrated relatively deeply into the cartilage of both young and old mice. The nanoparticles were just small enough to fit within the pores of the mice’s collagen networks, even the dense, cross-linked collagen of older animals.

Using a bioluminescent reporter, the researchers found out that this LNP treatment stays confined to where it needs to be and does not migrate to other organs, such as the liver, in appreciable amounts. Instead, it stays within the knee joint for approximately six days, and its effects diminish far slower than mRNA without LNP encapsulation. The LNP-mRNA was found to successfully cause cells to express significant amounts of the FGF18 protein.

This approach had significant beneficial effects in a cellular culture. Cellular senescence induced by the inflammatory cytokine IL-1β was cut approximately in half, as measured by p16, p21, p53, and SA-β-gal staining. Proliferation was approximately doubled as well. LNP-mRNA for FGF18 had very similar effects to pure FGF18 in this cellular experiment.

Autophagy was similarly upregulated. FOXO3 is downregulated when chondrocytes are exposed to IL-1β, but the LNP-mRNA was found to restore it nearly to the level of the control group. Cells that were only exposed to LNP-mRNA without IL-1β had even higher levels of FOXO3. This led to an increase of cartilage-producing proteins, and further experiments confirmed that this was due to an increase in autophagy.

After confirming its effects in cells, the researchers turned to mice: a control group, a group with a destabilized meniscus and no treatment, a group treated with FGF18 protein every week, and a group treated with LNP-mRNA every week. The damaged, untreated group was hypersensitive to pain, which was partially ameliorated by FGF18 and slightly moreso by the LNP treatment, although all of the damaged mice gradually got more sensitive to pain over eight weeks.

The LNP treatment was also found to benefit the mice’s gait and physical biomarkers, in both the destabilized meniscus model and in naturally aged mice. In many of the tests, there were no significant differences between FGF18-treated and LNP-treated mice, but there were some benefits to the new approach.

Most notably, the cartilage of the LNP-treated mice was significantly thicker, restoring the cartilage of damaged mice nearly to that of undamaged mice and, most critically, restoring the cartilage of aged mice nearly to that of young mice. A closer investigation found that the LNP injection was having the same effects in the mice as in the cellular culture, restoring proliferative capacity to the mice’s chondrocytes.

This is not a human study, but it appears that human trials are the next logical step for this approach, as it appears to be both safe and effective in animal models. Time will tell whether this particular LNP approach will be tested for the clinic or if it will undergo further refinement first.

Literature

[1] Davidson, D., Blanc, A., Filion, D., Wang, H., Plut, P., Pfeffer, G., … & Henderson, J. E. (2005). Fibroblast growth factor (FGF) 18 signals through FGF receptor 3 to promote chondrogenesis. Journal of Biological Chemistry, 280(21), 20509-20515.

[2] Boer, C. G., Hatzikotoulas, K., Southam, L., Stefánsdóttir, L., Zhang, Y., de Almeida, R. C., … & Wilkinson, J. M. (2021). Deciphering osteoarthritis genetics across 826,690 individuals from 9 populations. Cell, 184(18), 4784-4818.

[3] Gothard, D., Rotherham, M., Smith, E. L., Kanczler, J. M., Henstock, J., Wells, J. A., … & Oreffo, R. O. (2024). In vivo analysis of hybrid hydrogels containing dual growth factor combinations, and skeletal stem cells under mechanical stimulation for bone repair. Mechanobiology in Medicine, 2(4), 100096.

[4] Cinque, L., Forrester, A., Bartolomeo, R., Svelto, M., Venditti, R., Montefusco, S., … & Settembre, C. (2015). FGF signalling regulates bone growth through autophagy. Nature, 528(7581), 272-275.

[5] Evans, C. H., Kraus, V. B., & Setton, L. A. (2014). Progress in intra-articular therapy. Nature Reviews Rheumatology, 10(1), 11-22.

[6] Hajj, K. A., & Whitehead, K. A. (2017). Tools for translation: non-viral materials for therapeutic mRNA delivery. Nature Reviews Materials, 2(10), 1-17.

[7] Hou, X., Zaks, T., Langer, R., & Dong, Y. (2021). Lipid nanoparticles for mRNA delivery. Nature Reviews Materials, 6(12), 1078-1094.

As rejuvenation research advances from theory to practice, more therapies start making their way into the clinic. 2025 continues with both mouse experiments and human clinical trials.

Interviews

Cyclarity Launches Human Trial to Cure Atherosclerosis: Recently, Cyclarity Therapeutics announced the launch of a Phase 1 human clinical trial for a drug that aims to remove the arterial plaques that lead to heart attacks and strokes. Its primary cyclodextrin drug candidate, UDP-003, focuses on 7-ketocholesterol, a type of oxidized cholesterol that increases in cells and tissues as people age.

Marco Quarta on Cellular Senescence in Aging: Dr. Marco Quarta runs one of the most interesting start-ups in the longevity field: Rubedo, which focuses on utilizing the senolytic approach to cellular senescence. This company has developed ingenious ways to cope with the notorious heterogeneity of senescent cells and is one of the first to bring its senolytic drug candidate into clinical trials.

Advocacy and Analysis

The Battle for Long Life Has Been Accomplished: What’s Next?: How long can people live? This is not just a foundational question in science. The answer has important public policy implications and is of interest to us all. Recent scientific evidence has revealed the answer, so what’s next in humanity’s never-ending battle against disease and the persistent ravages of aging?

Research Roundup

Keeping Stem Cells Healthy and Young: A team of researchers has outlined a new approach that uses mRNA to prevent senescence and strengthen mesenchymal stem cells (MSCs) against aging before they are transplanted into patients.

A Potential Gene Therapy for Hearing Loss: In JCI Insight, researchers have explored the possibility of using gene therapy to restore a crucial protein and repair hearing loss. The most critical finding is that the adult cochlea, which processes hearing, is in fact capable of being remodeled through changes in gene expression after birth.

Drinking and Dying: Alcohol as a Risk Factor for Cancer: A new advisory by the US Surgeon General highlights a topic that – as the document itself notes – has been flying mostly under the public’s radar: the relationship between alcohol consumption and cancer.

Receiving Caloric Restriction Benefits Without Practicing It: In a new study, researchers have found that lithocholic acid, a metabolite found in the serum of calorically restricted mice, can mimic the effects of caloric restriction. While their research was conducted on model systems, they point to a previous study that observed that this metabolte was observed to be increased in the serum of healthy humans following 36 hours of fasting.

Precision Targeting of Senescent Cells: In a journal called Small, researchers have described a new targeting mechanism for delivering senolytic compounds where they need to go. These molecules are encapsulated in tiny soap bubbles rather than silica-based nanoparticles.

Intermittent Fasting Improves Coordination in Mice: Researchers have discovered that intermittent fasting increases myelin in aged mice, leading to better neural function and coordination. Normally, neuronal axons are coated in a protein sheath made of myelin, which is necessary for their proper function, but demyelination occurs in aging.

A Gut Metabolite Reduces Senescence and Inflammation: In a preprint study, scientists from Lifespan Research Institute and the Buck Institute for Research on Aging have published their findings that Urolithin A, a molecule that has garnered a lot of attention in the longevity field, potently reduces senescence-related markers in human fibroblasts.

The Impact of a Human Breast Milk Probiotic on Sarcopenia: The authors of this study, citing evidence of a link between the gut microbiome, muscle health, and sarcopenia, investigated the effect of the consumption of a probiotic on the muscle health of sarcopenia patients.

Enhancing NAD+ Efficiency by Energizing Sirtuins: Researchers publishing in Physical Review X have discovered compounds that can double the efficiency of the sirtuin SIRT3 in processing NAD+. Unlike previous efforts, this drug does not rely on a substrate to function.

New Study Links Epigenetic Changes to Genetic Mutations: A new paper published in Nature Aging suggests that somatic mutations cause significant remodeling of the epigenetic landscape. The findings might be relevant to future anti-aging interventions.

Fighting Alzheimer’s by Helping Neurons Consume Proteins: Researchers have found that kinesin family member 9 (KIF9), a protein that diminishes with aging, is instrumental in allowing cells to consume harmful proteins and fights Alzheimer’s in a mouse model.

Maintaining Telomeres Extends Lifespan in Mice: A recent study has found that the overexpression of telomerase reverse transcriptase (TERT), which is a subunit of telomerase, an enzyme essential for telomere maintenance, leads to lifespan extension in mice without significant side effects.

Maintaining Muscle by Restoring Gut Bacteria: In Aging Cell, researchers have described how different combinations of gut bacteria impact muscle strength in mice. The link between gut bacteria and health is well-documented, and multiple biomarkers have confirmed that a healthy gut leads to health elsewhere.

New Drug Eliminates Breast Cancer in Mouse Study: Researchers have discovered a small molecule that effectively kills cancer cells in the most prevalent type of breast cancer. The new drug could help against cancer recurrence and decrease the need for surgery.

Restoring Cellular Proliferation Through Exosomes: In Cell Metabolism, researchers have described how a microRNA (miRNA) derived from exosomes generated by human embryonic stem cells (hESCs) restores function and fights senescence in cell cultures and mice.

Ultrasound as a Tool to Eliminate Senescent Cells: A new study suggests that low-intensity pulsed ultrasound (LIPUS) can be beneficial in eliminating senescent cells through the recruitment and activation of immune cells. LIPUS is a technology that can be easily applied in the clinic.

Inhibiting a Fundamental Factor in Brain Inflammation: Researchers have devised a method of reducing brain inflammation by creating a long-lasting inhibitor of the inflammatory factor NF-κB. These researchers believe that it “may serve as a potent therapeutic agent against pathological age-related inflammatory processes, especially those that target macrophages and microglia.”

Artificially Grown Tissue Repairs Heart Failure in Monkeys: German scientists have created lab-grown “patches” of heart muscle tissue derived from pluripotent stem cells. Following a success with rhesus monkeys, they have obtained approval for a human trial.

Reducing functionally defective old HSCs alleviates aging-related phenotypes in old recipient mice: This study demonstrates the presence of “younger” HSCs in old mice and that aging-associated functional decline can be mitigated by reducing dysfunctional HSCs.

Tenascin-C promotes bone regeneration via inflammatory macrophages: Taken together, this study reveals the regulation of macrophage recruitment and its function in the activation of skeletal stem cells after bone injury, providing a strategy to accelerate bone regeneration by TNC delivery.

Innovative treatment of age-related hearing loss using MSCs and EVs with Apelin: These findings highlight the regenerative capabilities of MSCs and EV-mediated therapeutic approaches for this condition.

Delivery of FGF18 using mRNA-LNP protects the cartilage against degeneration via alleviating chondrocyte senescence: In summary, this study presents a novel approach superior to recombinant protein alone and holds promise as a new therapeutic strategy for OA.

Data-driven discovery of associations between prescribed drugs and dementia risk: A systematic review: Drug repurposing for use in dementia is an urgent priority. These findings offer a basis for prioritizing candidates and exploring underlying mechanisms.

Intestine-specific disruption of mitochondrial superoxide dismutase extends longevity: Combined, these results indicate that disruption of sod-2 in neurons, intestine, germline, or muscle is not required for lifespan extension, but that decreasing sod-2 expression in just the intestine extends lifespan.

Protection of Alzheimer’s disease progression by a human-origin probiotics cocktail: These results suggest that this unique probiotics cocktail could serve as a prophylactic agent to reduce the progression of cognitive decline and AD pathology.

The role of the Mediterranean diet in reducing the risk of cognitive impairement, dementia, and Alzheimer’s disease: a meta-analysis: These findings underscore the Mediterranean diet’s potential as a central element in neuroprotective public health strategies to mitigate the global impact of cognitive decline and dementia and to promote healthier cognitive aging.

Dietary carotenoid intakes and biological aging among US adults, NHANES 1999–2018: Increased dietary intakes of various carotenoids were associated with lower biological aging indices, which was possibly and mainly driven by lutein/zeaxanthin and β-carotene.

Multi-omics characterization of improved cognitive functions in Parkinson’s disease patients after the combined metabolic activator treatment: These results show that combined metabolic activator administration leads to enhanced cognitive function and improved metabolic health in Parkinson’s disease patients as recently shown in Alzheimer’s disease patients.

Combination of rapamycin and adipose-derived mesenchymal stromal cells enhances therapeutic potential for osteoarthritis: These findings suggest that the rapamycin and AD-MSC combination enhances the therapeutic efficacy of these cells in senescence-driven degenerative diseases such as OA, notably by improving their anti-fibrotic and anti-inflammatory properties.

Long-term intake of Tamogi-take mushroom (Pleurotus cornucopiae) mitigates age-related cardiovascular dysfunction and extends healthy life expectancy: Ingestion of Tamogi-take mushrooms could serve as a dietary intervention to promote cardiovascular health, support healthy aging and slow the progression of age-related diseases.

Ergothioneine improves healthspan of aged animals by enhancing cGPDH activity through CSE-dependent persulfidation: These findings elucidate this compound’s multifaceted actions and provide insights into its therapeutic potential for combating age-related muscle decline and metabolic perturbations.

Comprehensive evaluation of lifespan-extending molecules in C. elegans: These findings confirmed robust lifespan extension by many, but not all, of the 16 tested compounds from the literature and revealed that some of them could be combined to obtain additive effects.

Oct4, Sox2, Klf4, c-Myc (OSKM) gene therapy in the hypothalamus prolongs fertility and ovulation in female rats: Long-term OSKM gene therapy in the hypothalamus is able to extend the functionality of such a complex system as the hypothalamo-pituitary-ovarian axis.

Transcriptomic signatures and network-based methods uncover new senescent cell anti-apoptotic pathways and senolytics: Identifying new antiapoptotic resistance targets and drugs with potential senolytic activity paves the way for developing new pharmacological therapies to eliminate senescent cells selectively.

NAD World 3.0: the importance of the NMN transporter and eNAMPT in mammalian aging and longevity control: This approach features multi-layered feedback loops to provide a more comprehensive understanding of NAD.

Activation of Nuclear Receptor CAR: A Pathway to Delay Aging through Enhanced Capacity for Xenobiotic Resistance: These results suggest that the longevity effects of CAR agonists may be related to the enhancement of xenobiotic resistance of animals.

Long-Term Impact of Using Mobile Phones and Playing Computer Games on the Brain Structure and the Risk of Neurodegenerative Diseases: Lengthy mobile phone use is associated with a reduced risk of neurodegenerative diseases and improved brain structure compared to minimal usage.

News Nuggets

Vitalia Co-Founders Announce Split-up: Vitalia co-founders Niklas Anzinger and Laurence Ion today announced that they will be leading two new, separate organizations, Viva City and Infinita City. “Together, we built Vitalia from the ground up, establishing a foundation that has led us to this exciting new chapter,” said Anzinger and Ion in a joint statement.

Cyclarity Launches Human Trial for Atherosclerosis: Cyclarity Therapeutics, a biotechnology company based at the Buck Institute in California, has launched its first human clinical trial. Its primary candidate cyclodextrin drug, UDP-003, focuses on 7-ketocholesterol, an oxidized cholesterol variant that builds up in cells as we age.

Cutting-Edge Facility Expands to Support Cancer Therapy: New York Gov. Kathy Hochul and leaders from The Roswell Park Comprehensive Cancer Center came together on Monday to celebrate the opening of the newly expanded Roswell Park Good Manufacturing Engineering and Cell Manufacturing Facility (GMP).

New Database Lets You Know How Processed Your Food Is: Scientists have presented GroceryDB, an open-access online database that measures the degree of processing of tens of thousands of products sold in three major US grocery chains.

Coming Up

Founders Longevity Forum and NUS Announce Event: Founders Longevity Forum Singapore, hosted in collaboration with the National University of Singapore (NUS) Academy for Healthy Longevity, Yong Loo Lin School of Medicine, and Longevity.Technology is set to host a pivotal two-day event on 27-28 February 2025, in Singapore.

The Global Conference on Gerophysics: Chaired by Prof Brian Kennedy, Assoc Prof Jan Gruber and Dr Maximilian Unfried, this pioneering conference will bring together leading theoretical physicists and eminent researchers in ageing and rejuvenation biology to explore a transformative new field: ‘Gerophysics’.

The 3rd Longevity Med Summit Heads to Lisbon in May 2025: The Global 3rd Longevity Med Summit, the premier global event in longevity medicine, wellness, and healthcare innovation, is set to take place in Lisbon from May 6 to 8, 2025. This year’s summit promises an expanded agenda featuring groundbreaking topics, world-renowned speakers, and an exclusive Pre-Summit Day focused on the Future of Wellness.

Hevolution Foundation Hosts Second Global Healthspan Summit: On February 4-5, 2025, Hevolution Foundation will hold its second Global Healthspan Summit (GHS) in Riyadh, Saudi Arabia. The two-day event at the Four Seasons Hotel brings together international attendees, including world leaders, policymakers, researchers & scientists, and experts from the biotechnology, pharmaceutical, healthcare, and private sectors.