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A Likely Beneficial Compound Also Predicts Mortality

Researchers publishing in Aging have found that fibroblast growth factor 21 (FGF21), an apparently beneficial protein naturally produced by the human body, heralds a greater likelihood of death.

Multiple documented benefits

FGF21 plays crucial roles in the human body. Secreted by the liver and many other tissues, it is responsible for glucose maintenance and fat (lipid) metabolism [1]. Mimics of FGF21 have been found to have beneficial effects against diabetes and metabolic issues, such as cholesterol and triglyceride imbalances [2]. Further work has found that it may have even farther-ranging benefits [3], and its administration increases the lifespan of mice [4].

However, previous research has also found that animals that produce more FGF21 over time are more likely to die early [5], making it a potential biomarker of aging [6]. These researchers, therefore, took a step towards reconciling these facts, looking into the details of how FGF21 concentrations are correlated with mortality risk.

More FGF21, more mortality risk

This study was conducted using data from 3,512 people who were at least 50 years old, with a roughly even gender balance. The data was taken from a Polish source (PolSenior2), and the vast majority of participants were of European descent.

Participants were grouped into tertiles by FGF21 quantity and by sex, as women have more FGF21 than men. Men in the highest tertile were, on average, a year older than men in the middle, who, in turn, were a year older on average than men in the lowest. BMI, heart failure, diabetes, and biomarkers of lipid metabolic problems all rose with increasing FGF21. For women, the difference was even more drastic, although this can be accounted for because, in women, FGF21 and age were even more tightly linked.

FGF21, as expected, was linked with mortality, even after correcting for age. In an age-adjusted analysis, people in the middle group were 1.3 times as likely to die than the lower group; people in the higher group were nearly twice as likely. Even in a multivariable analysis that accounted for many other factors, people in the middle group were 1.2 times as likely to die, and people in the highest group were 1.5 times as likely. This molecule, despite being tested as a protector, was directly and independently associated with all-cause mortality.

This is not a fluke; this research is in line with other studies showing an association between FGF21 and mortality [7, 8]. This has led these researchers to carefully consider what might be driving their results. They hypothesize that FGF21 may be produced by the body in response to metabolic problems in an effort to counteract them; they also propose that FGF21 receptors might be being degraded with age, leading to an increase in its production but a decrease in its effectiveness. It is also questionable if FGF21 affects rodents and people in the same way. Further work will need to be done to determine if FGF21 is a druggable target in human beings.

We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.

Literature

[1] Chen, Z., Yang, L., Liu, Y., Huang, P., Song, H., & Zheng, P. (2022). The potential function and clinical application of FGF21 in metabolic diseases. Frontiers in pharmacology, 13, 1089214.

[2] Talukdar, S., Zhou, Y., Li, D., Rossulek, M., Dong, J., Somayaji, V., … & Calle, R. A. (2016). A long-acting FGF21 molecule, PF-05231023, decreases body weight and improves lipid profile in non-human primates and type 2 diabetic subjects. Cell metabolism, 23(3), 427-440.

[3] Tan, H., Yue, T., Chen, Z., Wu, W., Xu, S., & Weng, J. (2023). Targeting FGF21 in cardiovascular and metabolic diseases: from mechanism to medicine. International Journal of Biological Sciences, 19(1), 66.

[4] Zhang, Y., Xie, Y., Berglund, E. D., Coate, K. C., He, T. T., Katafuchi, T., … & Mangelsdorf, D. J. (2012). The starvation hormone, fibroblast growth factor-21, extends lifespan in mice. elife, 1, e00065.

[5] Tezze, C., Romanello, V., Desbats, M. A., Fadini, G. P., Albiero, M., Favaro, G., … & Sandri, M. (2017). Age-associated loss of OPA1 in muscle impacts muscle mass, metabolic homeostasis, systemic inflammation, and epithelial senescence. Cell metabolism, 25(6), 1374-1389.

[6] Hanks, L. J., Gutiérrez, O. M., Bamman, M. M., Ashraf, A., McCormick, K. L., & Casazza, K. (2015). Circulating levels of fibroblast growth factor-21 increase with age independently of body composition indices among healthy individuals. Journal of clinical & translational endocrinology, 2(2), 77-82.

[7] Conte, M., Ostan, R., Fabbri, C., Santoro, A., Guidarelli, G., Vitale, G., … & Salvioli, S. (2019). Human aging and longevity are characterized by high levels of mitokines. The Journals of Gerontology: Series A, 74(5), 600-607.

[8] Li, M., Jiang, L. Q., Zhang, M. Y., Liu, S. S., Sawh, R. R. R., Zheng, J., … & Wang, B. (2023). Elevated serum FGF21 is an independent predictor for adverse events in hemodialysis patients from two large centers: a prospective cohort study. Renal Failure, 45(2), 2256414.

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Metformin Slows Aging in Non-Human Primates

In a new study, metformin, which has already shown good results in rodents and in human epidemiological studies, alleviated multiple signs of aging in male cynomolgus monkeys [1].

Now in monkeys

Metformin, a well-established anti-diabetes drug, has been touted as a possible geroprotector since a study suggested that diabetes patients on metformin outlived age-matched healthy controls [2]. A newer study put these claims in doubt [3], but metformin is far from being dethroned.

While a rigorous study by the Interventions Testing Program (ITP) failed to produce life extension in mice on metformin [4], smaller studies have. In animal models, metformin has alleviated multiple hallmarks of aging, and it has also been linked to a reduction in health risks in humans. The ambitious Targeting Aging with Metformin (TAME) study is expected to shed more light on the drug’s effects, when and if it takes off the ground.

Meanwhile, a group of Chinese scientists performed a groundbreaking long-term study of metformin in cynomolgus monkeys. These relatively long-lived non-human primates match human biology much better than mice.

Improved cognitive function

The study lasted for 40 months and “encompassed a comprehensive suite of physiological, imaging, histological, and molecular evaluations” with 68 parameters overall. For their study group, the researchers took male cynomolgus monkeys aged 13 to 16 years, which is roughly equivalent to 40 to 50 human years. There were also three control groups: old, young, and middle-aged monkeys. The dose chosen was 20 mg/kg, which is a standard dosage for long-term anti-diabetes use in humans.

Metformin was mostly safe in these monkeys, just like in humans. The researchers periodically assessed multiple parameters and found that the treatment was associated with numerous health benefits. To begin with, the monkeys on metformin demonstrated better cognitive performance than age-matched controls in both memory and learning.

These results matched the analysis of cortical thickness in several brain regions. Compared to controls, which showed a decrease in cortical thickness with age, “in metformin-treated aged monkeys, frontal lobe cortical thickness was preserved, with a trend toward increased thickness in the parietal lobe,” the paper says.

Less transcriptomic aging and inflammation

Digging deeper into the mechanisms of metformin-related improvements, the researchers conducted organism-wide and genome-wide RNA sequencing, profiling 79 tissues and organs. They found that in terms of expression, genes in control groups could be divided into four clusters: expression goes down with age (D), expression goes up with age (U), expression goes up and then down (UD), and expression goes down then up (DU). In all four clusters, age-dependent changes were significantly mitigated by the treatment:

Metformin was also associated with decreased accumulation of senescent (p21-positive) cells in multiple tissues and with less fibrosis in the lung, kidney, and heart. There were signs of slower muscle aging and of increased epigenetic stability (lower endogenous retroviral activity).

“Strikingly,” the paper says, “we detected a widespread, potent effect of metformin in curbing chronic inflammation, a cardinal hallmark of aging that underlies almost all aging-related diseases.” Metformin was associated with reduced age-related inflammation in the liver and stomach. A reduction in immune cell infiltration was detected in the lung, liver, and kidney.

The clock ticks slower

The researchers constructed a set of biological age clocks using multi-omics data. Their analysis showed a 6.41-year reduction in biological age following metformin treatment, with the biggest reductions in the brain, lung, kidney, and liver. In all 13 tissues analyzed, the clock was reversed to some degree.

Several cell types were also analyzed in depth using single-nucleus transcriptomics. Mirroring the tissue-level results, hepatocytes (liver cells) and various brain cells showed the most robust slowing of biological age following the treatment.

Finally, the researchers reported that metformin reduced aging-associated periodontal bone loss. Not only is periodontal disease caused by aging, but it also probably exacerbates other aging processes by increasing inflammation [5].

Among the limitations of this study is its small sample size and its use of only male monkeys. This makes it harder to extrapolate the results to the female population, since females and males age differently.

Over 3 years, we evaluated metformin’s systemic geroprotective effects in healthy monkeys, taking advantage of their physiology and organ structure akin to humans, as well as their disease and medication responses. Our results indicate metformin’s capacity to ameliorate aging across the primate body, with multidimensional aging clocks showing a rejuvenation trend post-treatment… Our study reveals metformin’s tissue- and cell-specific geroprotective actions, notably enhancing cognitive performance in primates.

We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.

Literature

[1] Yang, Y., Lu, X., Liu, N., Ma, S., Zhang, H., Zhang, Z., … & Liu, G. H. (2024). Metformin decelerates aging clock in male monkeys. Cell.

[2] Bannister, C. A., Holden, S. E., Jenkins‐Jones, S., Morgan, C. L., Halcox, J. P., Schernthaner, G., … & Currie, C. J. (2014). Can people with type 2 diabetes live longer than those without? A comparison of mortality in people initiated with metformin or sulphonylurea monotherapy and matched, non‐diabetic controls. Diabetes, Obesity and Metabolism, 16(11), 1165-1173.

[3] Stevenson-Hoare, J., Leonenko, G., & Escott-Price, V. (2023). Comparison of long-term effects of metformin on longevity between people with type 2 diabetes and matched non-diabetic controls. BMC Public Health, 23(1), 804.

[4] Strong, R., Miller, R. A., Antebi, A., Astle, C. M., Bogue, M., Denzel, M. S., … & Harrison, D. E. (2016). Longer lifespan in male mice treated with a weakly estrogenic agonist, an antioxidant, an α‐glucosidase inhibitor or a Nrf2‐inducer. Aging cell, 15(5), 872-884.

[5] Hajishengallis, G., & Chavakis, T. (2021). Local and systemic mechanisms linking periodontal disease and inflammatory comorbidities. Nature Reviews Immunology, 21(7), 426-440.

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Insights from the Roundtable of Longevity Clinics 2024

The quest to extend human lifespan and improve healthspan is advancing rapidly, and one of the most prestigious platforms for driving these discussions is the Roundtable of Longevity Clinics. This annual gathering brings together global experts to exchange knowledge on cutting-edge research, innovations, and regulatory strategies aimed at enhancing human longevity.

The 2024 edition promises to be a groundbreaking event, assembling the most prominent longevity clinics and leading solution providers to discuss the gold standards in the industry. Together, they will create a unified voice for the longevity field, shaping the future of aging interventions.

Key Themes at the Roundtable of Longevity Clinics 2024

Longevity Medicine in Practice: This theme focuses on the real-world application of longevity interventions in clinical settings, discussing how to integrate cutting-edge treatments into everyday medical practice to improve healthspan.
Longevity Diagnostics: Understanding early biomarkers of aging is critical for intervention. This segment highlights breakthroughs in diagnostic tools, including biological clocks, epigenetic markers, and advanced medical imaging, which allow for personalized longevity plans.
Longevity Interventions: A deep dive into regenerative medicine, gene therapies, and other emerging treatments that aim to reverse or halt age-related decline. The section will also cover key lifestyle interventions, including sleep optimization, fasting, supplements, music therapy, and other approaches to enhance healthspan and longevity.
Digital Longevity: The role of digital tools, and machine learning in longevity research and practice. Discussions will center on how AI-driven insights are transforming personalized treatments and accelerating the discovery of new longevity therapies.
Client Engagement: Exploring how healthcare providers can maintain client engagement in long-term longevity programs, ensuring adherence to treatment protocols and sustained health improvements.
Longevity Roundtable: This event will feature dynamic panel discussions where representatives from leading longevity clinics and top service providers will explore current trends, cutting-edge diagnostic solutions, innovative interventions, and the business aspects of the rapidly evolving longevity industry.

Notable Speakers

The Roundtable of Longevity Clinics 2024 will feature an impressive lineup of leading experts, including:

Peter H. Diamandis (XPRIZE Foundation)
Dr. Eric Verdin (Buck Institute for Research on Aging)
Dr. Leroy Hood (Phenome Health)
Dr. Dean Ornish (Ornish Lifestyle Medicine)
Dr. Michael Roizen (Cleveland Clinic)
Dr. Andrea B. Maier (CHI Longevity)
Joanna Bensz (Longevity Center)

For more details, visit the official conference site. These thought leaders and many others will present their latest findings and explore the path to translating scientific discoveries into practical interventions that could redefine aging.

Why the Roundtable of Longevity Clinics Matters

With global life expectancy rising, extending healthspan is becoming a critical issue. The Roundtable of Longevity Clinics is a leading forum for shaping the future of aging. This event will aim to set new standards in longevity treatments, ensuring that the therapies and innovations discussed will accelerate how we approach aging and health. The ideas and collaborations formed here will help define the next generation of therapies capable of transforming how we age, making this conference essential for researchers, investors, and innovators alike. For entrepreneurs, the longevity field offers exciting growth opportunities—from biotechnology startups to AI-driven healthcare solutions. The insights gained at this conference could pave the way for significant economic expansion in the sector.

Join the Future of Longevity!

Get your ticket now for the Roundtable of Longevity Clinics 2024 and connect with world-leading experts. Don’t miss out— secure your spot today to be part of the conversations shaping the future of aging interventions!

How to Follow the Conference

Stay connected with the latest developments at the Roundtable of Longevity Clinics 2024 by following Lifespan.io for key takeaways, interviews, and insights. Join the conversation on social media using #LongevityRoundtable and #LifespanRevolution to be part of the global movement shaping the future of longevity.

On Social Media

Unlock the secrets to a longer, healthier life! The Roundtable of Longevity Clinics 2024 is happening soon, featuring top scientists, innovators, and thought leaders in human longevity. Stay tuned for exclusive coverage from Lifespan.io and get insights from the brightest minds in aging research. Let’s reshape the future of health together! #LongevityRoundtable #LifespanRevolution #HealthyAging #FutureOfLongevity

We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.