Mois : mai 2024

A debate titled “How to Defeat Aging” will be held on May 27, 2024, featuring two distinguished scientists, Peter Fedichev and Aubrey de Grey, both proponents of radical life extension with biotechnology, with opposing views.

Fedichev believes aging is irreversible but can be slowed or stopped, while de Grey argues for the potential of rejuvenation to reverse aging. The debate will discuss the feasibility of these approaches in light of recent scientific advancements and growing clinical evidence, aiming to determine which method can deliver clinical therapeutics that can significantly extend human life within the next 10 years. The event, hosted by the Foresight Institute, Say Forever, and Open Longevity, will be accessible both offline and online. The winner, chosen by a jury, will receive a $10,000 prize to further their research.

The Jury

Prof. David Furman (Buck/Stanford)
Prof. Dorota Skowronska-Krawczyk (UCI)
Prof. Guo Huang (UCSF)
Prof. Thomas Stoeger (Northwestern)
Prof. Mattew Yosefzadeh (Columbia)

The quest for longevity has captured human imagination for centuries. In recent years, significant advancements in science and technology have brought us closer to potentially revolutionary breakthroughs in the field of aging research. However, the path forward is not clear-cut, with two distinct and scientifically grounded schools of thought emerging:

Reversing Aging through Rejuvenation: Dr. Aubrey de Grey, a biomedical gerontologist with a PhD in Biology from Cambridge, is the leading proponent of the Strategies for Engineered Negligible Senescence (SENS). This comprehensive approach aims to repair and rejuvenate the human body at the cellular and molecular level by targeting seven categories of age-related damage: cell loss, division-obsessed cells, death-resistant cells, mitochondrial mutations, and the accumulation of intracellular, extracellular, and extracellular matrix waste products. De Grey’s premise is that aging is a disease that can be treated and potentially cured, just like any other ailment. He is President and Chief Science Officer of the LEV Foundation, a non-profit organization dedicated to advancing rejuvenation biotechnologies. A prolific speaker and author, he has co-founded multiple organizations, including the Methuselah Foundation and SENS Research Foundation, to accelerate research and development in this field. His work has garnered international recognition and sparked considerable debate, positioning him as a key figure in the longevity research landscape. .

Halting Aging by Managing Irreversible Damage: On the other side, Peter Fedichev, a co-founder of longevity biotech Gero, a physicist and gerontologist with a PhD in Theoretical Physics from the University of Amsterdam, proposes a different paradigm. Fedichev’s research, rooted in complex systems physics, has led him to link aging in humans with the inevitable accumulation of irreversible damage, akin to an increase in entropy. This theory suggests that while we may not be able to completely reverse aging using near-term technologies, we can potentially develop interventions to slow down or even halt the accumulation of damage, thereby significantly extending healthy lifespan. Peter has made several discoveries on what limits our ultimate lifespan and how to break this limit, which have been published in top peer-reviewed journals and featured by numerous media outlets, including Scientific American and Popular Mechanics. Fedichev’s theory is now the basis of an AI drug-discovery platform, used by Gero.ai for in-house drug pipeline and collaborations with pharmaceutical companies, including Pfizer. Dr. Fedichev on X.

The co-organizer of the debate, Open Longevity, provides more details about the event, research, and the positions of the opponents. Visit https://openlongevity.org/debates for more information.

To attend in person at The Foresight Institute, sign up here
Watch the live YouTube broadcast here
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Publishing in Aging, a team of researchers has used a rat model to investigate a possible reason why old people are less able to learn new things.

A critical receptor

This paper begins with a discussion of receptors for N-methyl-D-aspartate (NMDA), a compound that affects multiple aspects of cognition, most notably neuroplasticity: the brain’s ability to learn new things [1]. NMDA function is well-known to decline with age, and a substantial amount of research has been conducted on the relationship to overall brain function [2].

To be activated, the NMDA receptor requires the binding of two separate compounds: the common amino acid glutamate and, principally, the more specific agonist D-serine [3]. D-serine is formed from the conversion of L-serine through serine racemase (SR) [4], a compound that is secreted by the neuroglia. Interestingly, this secretion can be heightened under stress conditions, such as injury [5] and the presence of amyloid precursors [6].

How SR production declines with age

These researchers used rat models to take a closer look at SR. First, they examined the brains of Fischer 344 rats, a standard breed of wild-type animals. 26-month-old rats, as expected, had significantly less SR than 5-month-old rats throughout the prefrontal cortex, a brain region critical for learning and cognition, as well as the hippocampus, which is responsible for memory. While the effects were significant in both male and female rats, the effects were exceptionally strong in the CA1, a specific part of the hippocampus, in male rats.

The researchers also discovered a potential measurement issue. β-actin is a common protein that is often used as a reference with which to measure other proteins. However, β-actin is also different between older males and older females in the prefrontal cortex.

As these researchers have previously used a viral vector to improve cognition in middle-aged rats by upregulating SR [7], these results shed more light on what age-related changes could potentially be reversed by such a treatment. As male and female rats express SR differently, it would be crucial to take sex differences into account if a clinical trial for increasing SR is performed on human beings.

Literature

[1] Zorumski, C. F., & Izumi, Y. (2012). NMDA receptors and metaplasticity: mechanisms and possible roles in neuropsychiatric disorders. Neuroscience & Biobehavioral Reviews, 36(3), 989-1000.

[2] Foster, T. C. (2012). Dissecting the age-related decline on spatial learning and memory tasks in rodent models: N-methyl-D-aspartate receptors and voltage-dependent Ca2+ channels in senescent synaptic plasticity. Progress in neurobiology, 96(3), 283-303.

[3] Papouin, T., Ladépêche, L., Ruel, J., Sacchi, S., Labasque, M., Hanini, M., … & Oliet, S. H. (2012). Synaptic and extrasynaptic NMDA receptors are gated by different endogenous coagonists. Cell, 150(3), 633-646.

[4] Wolosker, H., Blackshaw, S., & Snyder, S. H. (1999). Serine racemase: a glial enzyme synthesizing D-serine to regulate glutamate-N-methyl-D-aspartate neurotransmission. Proceedings of the National Academy of Sciences, 96(23), 13409-13414.

[5] Perez, E. J., Tapanes, S. A., Loris, Z. B., Balu, D. T., Sick, T. J., Coyle, J. T., & Liebl, D. J. (2017). Enhanced astrocytic d-serine underlies synaptic damage after traumatic brain injury. The Journal of Clinical Investigation, 127(8), 3114-3125.

[6] Wu, S., Basile, A. S., & Barger, S. W. (2007). Induction of serine racemase expression and D-serine release from microglia by secreted amyloid precursor protein (sAPP). Current Alzheimer Research, 4(3), 243-251.

[7] Yegla, B., Rani, A., & Kumar, A. (2023). Viral vector-mediated upregulation of serine racemase expression in medial prefrontal cortex improves learning and synaptic function in middle age rats. Aging (Albany NY), 15(7), 2433.

A paper published in Age and Ageing analyzed the intake of different food groups and whether they accelerate or decelerate biological age in post-menopausal women [1].

Nutrition and biological age

Biological age is a better indicator of health and aging than chronological age [2]. Multiple measurements can be used to assess biological age; some of the most common include epigenetic clocks. Based on changes in age-related DNA methylation patterns, those clocks can estimate the difference between chronological and biological age, which indicates age acceleration or deceleration.

Since recent studies suggest a small role (10-16%) of heritability in longevity [3, 4], other factors, such as lifestyle and environment, must play significant roles in biological aging. One such factor is nutrition. However, the authors note that data linking dietary interventions and biological age changes is not always consistent, and studies on this topic have many caveats, such as small sample sizes, the use of different epigenetic clocks, or a focus on a single nutrient.

The authors of this study decided to take a different approach. They used a large database and focused on food groups that might affec biological aging. They also used a statistical method emphasizing “exploration and identification, as opposed to methods focused on magnitude and causality.”

The researchers used data on 3,990 women from the Women’s Health Initiative (WHI) cohort, which includes postmenopausal women of different ethnicities based in North America. The mean chronological age of the study participants was 63.3 years. The data included their dietary intake based on the WHI Food Frequency Questionnaire.

What to eat or not to eat

The analysis revealed an association between decelerated aging and the consumption of peaches/nectarines/plums, poultry, nuts, and discretionary fat (solid and oil). On the other hand, consumption of eggs, organ meat, sausages, cheese, legumes, starchy vegetables, added sugar, lunch meat, and fat added after cooking showed an association with accelerated biological aging.

Some of the observations were expected and didn’t surprise the authors; for example, the positive effect of poultry and nuts on aging was unsurprising, as it agrees with previous research [5, 6]. However, some were unexpected or quite complex.

The authors found it interesting that such foods as peaches, nectarines, and plums were associated with decreased age acceleration. While it makes sense that the intake of fruits, which are sources of many vitamins and phenolic compounds with antioxidant properties, would help slow aging, the authors think that there is more to this. Since fruits from this category are not the most commonly eaten, the authors hypothesize that people who consume them would also consume a high amount of other fruits and lead a healthy lifestyle, thus leading to biological age deceleration.

On the opposite side are potatoes and starchy vegetables, which were associated with age acceleration. The authors hypothesize that these vegetables might contribute to age acceleration due to a lack of fiber resulting in higher caloric intake due to less satiety feeling, a relatively high glycemic load leading to negative health outcomes, and reduced antioxidant activity as a result of processing.

The complex role of fat consumption

The authors discuss the negative impact of eggs and organ meat on biological age, which can be linked to their high cholesterol, protein, and fat content. They cited studies that link cholesterol and saturated fat to non-alcoholic fatty liver disease and cardiovascular disease [7, 8, 9]. Additionally, protein is known to activate mTOR, the master regulator of metabolism. Its activation negatively impacts longevity.

Fat added after cooking (such as butter, margarine, sour cream, or oils added to vegetables, beans, rice, and potatoes) was found to be associated with increased biological age. This observation, as researchers add, “aligns with the findings that excessive intake of high-fat foods may contribute to higher body weight and metabolic dysfunction” [10].

However, the longevity-fat consumption relationship seems to be quite complex and nuanced. The authors mention that the association between solid fats and decelerated aging “was rather unexpected.” That food group includes such items as butter and dairy-derived fats along with other foods rich in saturated fatty acids, which are commonly regarded as something that should be minimized. However, the authors discuss that recent research has put that recommendation into question. They cite studies that show no beneficial effects of saturated fatty acid consumption on cardiovascular disease and mortality [11], with some suggesting risk reduction [12].

This conundrum requires more in-depth investigation with a study that would differentiate different types of fats in the analysis; this study did not go that far.

Other variables, limitations, and next steps

The researchers also analyzed variables beyond food and found an association between decelerated aging and diastolic blood pressure, education, and osteoporosis. Accelerated ageing was associated with systolic blood pressure, BMI, waist-to-hip ratio, smoking pack-years, cardiovascular disease, and arthritis. These researchers also found that Native Americans and Asians in this cohort aged more rapidly on average.

While the mathematical model used by the researchers had many strengths, as with every model, it has its limitations. Those include the inability to assess the magnitude of relationships and “the inability to infer causality or direction of relationships.” However, as the authors discuss, while there is still a need to prove the causality between food intake and biological age, the possibility that changes in epigenetic age would cause changes to dietary intake is unlikely.

The authors also point out that other variables not considered during the analysis, such as food processing, eating rate, and income level, might impact the results. They advise that their findings should be investigated in other cohorts to see if these results are particular only to this group. They also advise further research into which food processes, such as additives or smoking meats, impact health.

Literature

[1] Biemans, Y., Bach, D., Behrouzi, P., Horvath, S., Kramer, C. S., Liu, S., Manson, J. E., Shadyab, A. H., Stewart, J., Whitsel, E. A., Yang, B., de Groot, L., & Grootswagers, P. (2024). Identifying the relation between food groups and biological ageing: a data-driven approach. Age and ageing, 53(Supplement_2), ii20–ii29.

[2] Dodig, S., Čepelak, I., & Pavić, I. (2019). Hallmarks of senescence and aging. Biochemia medica, 29(3), 030501.

[3] Kaplanis, J., Gordon, A., Shor, T., Weissbrod, O., Geiger, D., Wahl, M., Gershovits, M., Markus, B., Sheikh, M., Gymrek, M., Bhatia, G., MacArthur, D. G., Price, A. L., & Erlich, Y. (2018). Quantitative analysis of population-scale family trees with millions of relatives. Science (New York, N.Y.), 360(6385), 171–175.

[4] Ruby, J. G., Wright, K. M., Rand, K. A., Kermany, A., Noto, K., Curtis, D., Varner, N., Garrigan, D., Slinkov, D., Dorfman, I., Granka, J. M., Byrnes, J., Myres, N., & Ball, C. (2018). Estimates of the Heritability of Human Longevity Are Substantially Inflated due to Assortative Mating. Genetics, 210(3), 1109–1124.

[5] Connolly, G., Clark, C. M., Campbell, R. E., Byers, A. W., Reed, J. B., & Campbell, W. W. (2022). Poultry Consumption and Human Health: How Much Is Really Known? A Systematically Searched Scoping Review and Research Perspective. Advances in nutrition (Bethesda, Md.), 13(6), 2115–2124.

[6] Zuelch, M. L., Radtke, M. D., Holt, R. R., Basu, A., Burton-Freeman, B., Ferruzzi, M. G., Li, Z., Shay, N. F., Shukitt-Hale, B., Keen, C. L., Steinberg, F. M., & Hackman, R. M. (2023). Perspective: Challenges and Future Directions in Clinical Research with Nuts and Berries. Advances in nutrition (Bethesda, Md.), 14(5), 1005–1028.

[7] Ioannou G. N. (2016). The Role of Cholesterol in the Pathogenesis of NASH. Trends in endocrinology and metabolism: TEM, 27(2), 84–95.

[8] Jung, E., Kong, S. Y., Ro, Y. S., Ryu, H. H., & Shin, S. D. (2022). Serum Cholesterol Levels and Risk of Cardiovascular Death: A Systematic Review and a Dose-Response Meta-Analysis of Prospective Cohort Studies. International journal of environmental research and public health, 19(14), 8272.

[9] Meex, R. C. R., & Blaak, E. E. (2021). Mitochondrial Dysfunction is a Key Pathway that Links Saturated Fat Intake to the Development and Progression of NAFLD. Molecular nutrition & food research, 65(1), e1900942.

[10] Julibert, A., Bibiloni, M. D. M., Mateos, D., Angullo, E., & Tur, J. A. (2019). Dietary Fat Intake and Metabolic Syndrome in Older Adults. Nutrients, 11(8), 1901.

[11] Astrup, A., Magkos, F., Bier, D. M., Brenna, J. T., de Oliveira Otto, M. C., Hill, J. O., King, J. C., Mente, A., Ordovas, J. M., Volek, J. S., Yusuf, S., & Krauss, R. M. (2020). Saturated Fats and Health: A Reassessment and Proposal for Food-Based Recommendations: JACC State-of-the-Art Review. Journal of the American College of Cardiology, 76(7), 844–857.

[12] de Oliveira Otto, M. C., Nettleton, J. A., Lemaitre, R. N., Steffen, L. M., Kromhout, D., Rich, S. S., Tsai, M. Y., Jacobs, D. R., & Mozaffarian, D. (2013). Biomarkers of dairy fatty acids and risk of cardiovascular disease in the Multi-ethnic Study of Atherosclerosis. Journal of the American Heart Association, 2(4), e000092.