AI vs humans in healthcare questions | Lifespan Research Institute

Date Posted: May 3, 2023

AI Better Than Humans At Healthcare Questions

Scientists have compared doctor-written and chatbot-generated responses to healthcare-related questions, and the results don’t look good for Team Human [1].

Ask your doctor?

Access to healthcare has been linked to longer lifespan, and good healthcare often starts with a good initial consultation. A group of researchers, including scientists from the University of California, San Diego and from the company Human Longevity, has set out to determine if AI might be able to do this better than human beings. The results were published in JAMA Internal Medicine.

The researchers based their study on 195 real-life exchanges from the Reddit forum r/AskDocs. In all instances, the initial questions asked by users were answered by verified physicians. Questions answered by other healthcare professionals were omitted on the premise that a response by a licensed physician constitutes a better benchmark. The researchers then posited same questions to the 3.5 version of ChatGPT that’s been around since November last year. Each question was asked in a new chat session.

Both the responses provided by human physicians and those provided by the AI model were then evaluated by a team of licensed healthcare professionals using several criteria. The evaluators considered “the quality of information provided” (very poor, poor, acceptable, good, or very good) and “the empathy or bedside manner provided” (not empathetic, slightly empathetic, moderately empathetic, empathetic, and very empathetic). The responses were, of course, randomized, stripped of any identifying information such as “I am an AI model”, and labeled “Response 1” and “Response 2”. To decrease the possibility of bias, each case was presented to three different teams of healthcare professionals for a total of 585 evaluations.

The machine prevails

The differences between the human-generated and the machine-generated responses began with their length. The AI gave significantly longer answers on average (211 words vs 52 words). Human professionals were not inclined to engage in a prolonged conversation: 94% of the exchanges contained a single response from the physician.

The evaluators preferred the chatbot response in a staggering 78.6% of cases. Chatbot responses reached the average score of 4.13 (better than “good”) and human responses 3.26 (worse than “good”). Moreover, 27% of human responses, but only 2.6% of machine responses, were rated “unacceptable” (less than 3). ChatGPT also cleanly defeated human physicians in the percentage of responses rated “good” or “very good”: 75.5% vs only 22% on Team Human.

As if this wasn’t enough, chatbot responses were also found to be significantly more empathetic (3.65 vs 2.15). A full 80.5% of human responses and just 15% of chatbot responses scored below “slightly empathetic” (less than 3). Chatbot responses were also almost 10 times likelier to be rated “sympathetic” or “very sympathetic”.

Let’s ask the chatbot

To explain these staggering results, we asked ChatGPT version 4.0 for its own analysis.

The chatbot then offered several important caveats:

Moreover, ChatGPT was empathetic enough to provide some comfort to us, humans, and show understanding of the circumstances many healthcare professionals find themselves in:

The researchers mention several limitations of their study, the most important being that an exchange on an online forum does not recapitulate a face-to-face dialogue between a patient and a physician. In such dialogue, the physician can expand on the topic, ask follow-up questions, provide increasingly more relevant information, and probably be more empathetic as well.

Additionally, the sample size was limited, and some of the co-authors were also on the evaluation team, which might have created bias despite the study’s blind design. Finally, it is possible that not all human physicians in the study were native English speakers, and the language barrier could have added to the impression of brevity and dispassion.

Conclusion

Based on the results of this study, the researchers call for an evaluation of the possibility to integrate chatbots into clinical settings. While chatbots cannot replace human healthcare professionals (at least for now), they might, the authors suggest, be employed in drafting messages to the patients to be edited and approved by the human staff.

In developing countries, where people often have only limited access to human healthcare professionals, chatbots might be even more important for providing initial assessment and assistance. Last but not least, chatbot-generated responses to healthcare questions might be able to counteract the copious amounts of incomprehensible, contradictory, or plainly misleading information that a regular web search often yields.

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Literature

[1] Ayers JW, Poliak A, Dredze M, et al. Comparing Physician and Artificial Intelligence Chatbot Responses to Patient Questions Posted to a Public Social Media Forum [published online ahead of print, 2023 Apr 28]. JAMA Intern Med. 2023

Date Posted: May 2, 2023

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Certain Medications Appear to Improve Aging Biomarkers

A twin study published in GeroScience has yielded results suggesting that calcium channel blockers, drugs that are commonly used to treat hypertension and other diseases, slow down epigenetic aging and may lengthen healthy lifespan.

A wide field

The researchers begin this paper by noting that over 400 compounds, as found in the DrugAge database, have been reported to extend lifespan in model organisms [1]. However, getting human data for the efficacy of these drugs against any of the processes of aging is considerably more difficult. Therefore, researchers normally try use surrogate endpoints that correspond to lifespan (biomarkers) [2].

Some drugs, however, already appear to be associated with lifespan. The researchers placed their focus on antihypertensive, antidiabetic, and lipid-lowering drugs, which are widely consumed by a substantial fraction of the US population [3], have been reported to have beneficial effects against other age-related diseases: statins are linked to a reduced incidence of dementia [4] and metformin is linked to a decrease in cancer incidence [5].

Previous studies have attempted to examine the relationship between these sorts of drugs and DNA methylation clocks [6]. However, while these clocks are valuable, they are not always comprehensively robust, and so these researchers aimed to use considerably more biomarkers.

A robust twin study with multiple layers of information

This paper uses data from SATSA, a Swedish twin study that focuses on twins that were raised together or apart. Participants who were at least 50 years old received in-person examinations for 3 years between 1986 and 2014, creating a wide body of evidence. After exclusions for contradictory or incomplete information, 672 people with 2,746 measurements were included in the results analyzed here.

There were a total of 12 different biomarkers, including measurements of DNA methylation (including DunedinPACE and GrimAge), telomere length, physical frailty, functional age, and cognitive decline. Many of these biomarkers were composites of related biomarkers. The medications taken by the participants were self-reported, which was corroborated by purchase data.

Advanced statistical analysis was performed on these results, controlling for confounding variables and correlating multiple drugs. As this was a long-term study, it was possible to conduct individual analyses, comparing people’s measurements before and after they were consuming certain medications. The researchers’ model also took into account the diseases that had caused the participants to be taking such medications in the first place.

A confluence of factors

Unsurprisingly, the people who did and didn’t take medications of all types had significant demographic differences. Medication takers were older and had higher BMIs and blood pressure.

Depending on how the researchers analyzed their measurements at the individual level, certain patterns began to emerge. The number of participants who took antidiabetic drugs was too low to draw any significant conclusions. However, in a model that controlled for individual biases, antihypertensive drugs were found to be associated with a lower GrimAge.

While some antihypertensive drugs were individually found to be associated with better cognition but negative effects on epigenetic aging, calcium channel blockers were associated with multiple functional biomarkers along with decreased methylation aging according to multiple epigenetic clocks.

Conclusion

This study is interesting for both its positive and negative results. With statistical results such as these, the biological effects of calcium channel blockers on human beings warrant further investigation. On the other hand, these results make it clear that while they are effective against the specific disorders that they are prescribed for, the vast majority of drugs do not appear to have any noticeable effects on biological aging.

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Literature

[1] Barardo, D., Thornton, D., Thoppil, H., Walsh, M., Sharifi, S., Ferreira, S., … & de Magalhães, J. P. (2017). The DrugAge database of aging‐related drugs. Aging cell, 16(3), 594-597.

[2] Lohman, T., Bains, G., Berk, L., & Lohman, E. (2021). Predictors of biological age: The implications for wellness and aging research. Gerontology and Geriatric Medicine, 7, 23337214211046419.

[3] Hales, C. M., Servais, J., Martin, C. B., & Kohen, D. (2019). Prescription drug use among adults aged 40–79 in the United States and Canada.

[4] Jick, H. Z. G. L., Zornberg, G. L., Jick, S. S., Seshadri, S., & Drachman, D. A. (2000). Statins and the risk of dementia. The Lancet, 356(9242), 1627-1631.

[5] Gandini, S., Puntoni, M., Heckman-Stoddard, B. M., Dunn, B. K., Ford, L., DeCensi, A., & Szabo, E. (2014). Metformin and Cancer Risk and Mortality: A Systematic Review and Meta-analysis Taking into Account Biases and ConfoundersMetformin Meta-Analysis. Cancer prevention research, 7(9), 867-885.

[6] Gao, X., Colicino, E., Shen, J., Just, A. C., Nwanaji-Enwerem, J. C., Coull, B., … & Baccarelli, A. A. (2018). Accelerated DNA methylation age and the use of antihypertensive medication among older adults. Aging (Albany NY), 10(11), 3210.

Date Posted: May 2, 2023

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Flavonols, Especially Quercetin, Linked to Less Frailty

In a new prospective cohort study, a higher intake of flavonols, and quercetin in particular, was linked to a significant decrease in the risk of frailty [1].

Flavonoids: not just flavor

Flavonoids are a class of polyphenolic compounds that include flavanols, flavonols, flavones, anthocyanins, and some others. Flavonoids are abundant in plant-based foods, including fruits, vegetables, berries, grains, tea, and wine. They have been studied extensively for their potential health benefits, including antioxidant, anti-inflammatory, and anti-cancer effects. In a recent study, flavanols found in cocoa extract were found to reduce cardiovascular mortality.

One flavonol called quercetin has been an object of increased interest for geroscientists. Its combination with the cancer drug dasatinib, D+Q, is a popular senolytic approach that has shown some success in preclinical and clinical trials [2]. Quercetin reduces oxidative stress and even increases lifespan in several organism models [3]. Quercetin is the most abundant in onions but most bioavailable in berries.

Flavonoids and frailty

This new prospective cohort study attempted to elucidate the role of flavonoids, their subclasses, and quercetin in particular in the prevention of frailty, a clinical syndrome that is characterized by a decline in physiological reserves and function across multiple organ systems. This decline contributes to morbidity and mortality by leaving the person vulnerable to sudden changes in health status triggered by relatively minor stressor events. Frailty is also a major cause of falls and impaired mobility in the elderly.

A recent meta-analysis has found that a healthy diet rich in flavonoids (such as the Mediterranean diet) might decrease the risk of frailty by 50% to 70% [4]. There have been also some interventional studies that showed a positive effect of flavonoids on frailty-related symptoms. In one such study, supplementation with blueberries, a rich source of flavonoids, led to gait improvements in elderly people [5].

Quercetin lives up to expectations

This new study was based on the Framingham Heart Study and encompassed 1701 participants with no frailty at baseline (1998-2001). Frailty was then re-evaluated in 2011–2014. Levels of flavonoid intake were estimated using a food intake questionnaire. The sample was roughly equally distributed by sex, and the mean age at baseline was 58.4. Over an average of 12 years of follow-up, 13.2% of the participants developed frailty.

In a model adjusted for sex, age, energy intake, smoking status, cancer, cardiovascular health, and diabetes, the association between frailty and overall flavonoid intake was insignificant. However, when researchers dug deeper into individual subclasses of flavonoids, the picture became clearer. Each 10 milligram per day increase in flavonol intake was associated with a 20% decrease in the risk of developing frailty. Even more impressively, each 10 milligram per day increase in quercetin intake was associated with 35% lower odds of frailty onset.

Another significant result was age-dependent: among the participants younger than 60 years old, each 10 milligram per day increase in the intake of anthocyanins, another subtype of flavonoids that gives many fruits and vegetables their blue, purple, or black color, was associated with 52% lower odds of frailty onset. However, for participants aged 60 years and older, no significant association was observed.

Like any populational study, this one was laden with limitations, such as using a questionnaire to assess nutrient intake at a single time point along with having a relatively small sample size. However, such studies allow researchers to assess the effects of long-term dietary habits, which is nearly impossible in interventional studies.

In this prospective cohort study, although flavonoid intake was not significantly associated with the odds of frailty onset in middle-aged and older adults, higher intake of the flavonoid subclass, flavonols, was associated with reduced odds of frailty onset, which appeared to be driven by the specific flavonol, quercetin. The protective association between anthocyanins and frailty onset was primarily seen in participants below the age of 60 y. Although hypothesis-generating, this study highlights the potential of dietary flavonols and quercetin as a strategy to prevent frailty onset. Future research should focus on dietary interventions of flavonols or quercetin for treating frailty.

Conclusion

This interesting study suggests that not all flavonoids are equally protective against the onset of frailty, but some might have a robust effect. It confirms the known role of quercetin as a protector against various age-related conditions, which is likely due to its antioxidant activity. The results also highlight yet again the overall relevance of diet for healthspan.

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Literature

[1] Oei, S., Millar, C. L., Nguyen, T. N., Mukamal, K. J., Kiel, D. P., Lipsitz, L. A., … & Sahni, S. (2023). Higher intake of dietary flavonols, specifically dietary quercetin, is associated with lower odds of frailty onset over 12-years of follow-up among adults in the Framingham Heart Study. The American Journal of Clinical Nutrition.

[2] Hickson, L. J., Prata, L. G. L., Bobart, S. A., Evans, T. K., Giorgadze, N., Hashmi, S. K., … & Kirkland, J. L. (2019). Senolytics decrease senescent cells in humans: Preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease. EBioMedicine, 47, 446-456.

[3] Proshkina, E., Lashmanova, E., Dobrovolskaya, E., Zemskaya, N., Kudryavtseva, A., Shaposhnikov, M., & Moskalev, A. (2016). Geroprotective and radioprotective activity of quercetin,(-)-epicatechin, and ibuprofen in Drosophila melanogaster. Frontiers in pharmacology, 7, 505.

[4] Wang, Y., Hao, Q., Su, L., Liu, Y., Liu, S., & Dong, B. (2018). Adherence to the Mediterranean diet and the risk of frailty in old people: a systematic review and meta-analysis. The journal of nutrition, health & aging, 22, 613-618.

[5] Schrager, M. A., Hilton, J., Gould, R., & Kelly, V. E. (2015). Effects of blueberry supplementation on measures of functional mobility in older adults. Applied Physiology, Nutrition, and Metabolism, 40(6), 543-549.

Date Posted: May 1, 2023

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Dr. Peter Attia on How to Outlive

Peter Attia, M.D., popular host of The Drive, has nearly a million followers across his social media platforms. In his first book, OUTLIVE The Science and Art of Longevity, he summarizes much of the evidence and wisdom that he has delivered to his audience over the years by providing a no-nonsense evidence-based tactical manual for optimizing healthspan.

A matter of risk

The book opens with a brief recounting of the practice of medicine through the ages, emphasizing how the system has evolved to address acute illness and injury but not sensibly assess and manage the risks associated with the major metabolic diseases that account for 80% of deaths in people over 50 who do not smoke: atherosclerotic disease, cancer, neurodegenerative disease, and metabolic disease.

Attia reinforces this point by noting that once we account for people who were spared from death by infectious disease, life expectancy has only changed marginally since 1900. From here, Attia introduces the basic concepts of what he terms Medicine 3.0: prevention, personalization, and intelligent risk assessment.

The failure to estimate risk over longer time horizons is cited as a major fault of traditional medical practice, which does not address the major metabolic diseases at their inception but waits until those diseases are developed to the point at which the costs of intervention are much higher and more likely to fail.

A roadmap to healthspan

Attia unfurls a tactical roadmap to optimize healthspan. The first step is to concretely envision our future centenarian selves. What functional capacities do we imagine we’re going to have at 90 without a plan? Is our current trajectory likely to take us there? Attia explains how those answers are obtained through a thorough process of risk assessment, functional testing, and education.

Attia’s strategy of optimizing healthspan requires a focus on its three primary vectors: cognitive ability, physical function, and emotional health. If any of these component parts of healthspan are neglected, the idea of meaningful longevity is lost.

Part II discusses the strategy for optimizing lifespan in greater detail and the science that informs it. Attia addresses what we can learn from centenarian studies and how it is possible to capture the cognitive, functional, and emotional characteristics of centenarians without necessarily having the best genes.

Next, the author tackles the topic of caloric restriction before moving on to sharing his insights into the mechanisms underlying aging and how they are related to the development of diabetes, cardiovascular disease, and neurodegenerative disease. How and when do they begin? What forces drive them? Most importantly, how can they be delayed or even prevented entirely?

The strategy in detail

In Part III of OUTLIVE The Science and Art of Longevity, Peter Attia presents a comprehensive set of tactics in five main areas to optimize healthspan and longevity. These tactics, based on evidence and practical wisdom, are designed to help people achieve their envisioned future selves at 90 and beyond.

Exercise: Attia emphasizes the importance of incorporating a balanced mix of aerobic and anaerobic exercises, including Zone 2 and Zone 5 training, strength training, and flexibility/mobility workouts. These diverse exercise routines contribute to improved cardiovascular health, increased muscle mass, enhanced flexibility, and reduced risk of chronic diseases.

Nutrition: Attia advocates for a whole-foods-based diet rich in vegetables, lean proteins, healthy fats, and complex carbohydrates, with a focus on limiting processed foods and added sugars. He also discusses the potential benefits of intermittent fasting, time-restricted feeding, and caloric restriction in promoting cellular repair, metabolic health, and longevity. Personalization of dietary plans based on individual needs and genetics is a key aspect of his recommendations.

Sleep: Recognizing the critical role of sleep in overall health, Attia provides strategies for optimizing sleep quality and quantity. These include maintaining a consistent sleep schedule, creating a sleep-conducive environment, and addressing sleep disorders through appropriate medical interventions.

Emotional Health: Attia underscores the necessity of nurturing emotional well-being for a fulfilling, long life. He suggests practicing mindfulness techniques, such as meditation and gratitude journaling, prioritizing social connections, and engaging in leisure activities to foster emotional resilience and reduce stress.

Exogenous Molecules: Attia explores the potential benefits of carefully selected drugs, hormones, and supplements in addressing nutrient deficiencies, optimizing hormone levels, and promoting overall health. Some examples include fish oil, vitamin D, magnesium, and metformin. He advises consulting a healthcare professional before starting any new supplement or medication regimen.

Conclusion

Peter Attia’s OUTLIVE The Science and Art of Longevity offers a practical and evidence-based manual for people who want to to optimize their healthspan and achieve meaningful longevity. Through the application of Medicine 3.0 principles—prevention, personalization, and intelligent risk assessment—readers are empowered to take control of their health trajectories and work towards realizing their envisioned centenarian selves.

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Date Posted: May 1, 2023

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Rejuvenation Roundup April 2023

As the second month of spring, April is often associated with rebirth, and we’ve added rejuvenation to the mix with cryptocurrency donation initiatives, biotechnology company progress, and plenty of science.

LEAF News

A Busy Spring for Rejuvenation Research and Advocacy: Lifespan.io’s birthday was in April, and we proudly celebrated nine years of being a non-profit organization that advocates, educates, and fundraises for healthy life extension.

An Opportunity to Support Aging Research with Gitcoin: We have two scientific research projects in the new Gitcoin fundraising round. Help us to combat Alzheimer’s disease or improve how clinical trials are conducted today! Gitcoin is a decentralized science (DeSci) platform that utilizes blockchain technology to support the development of open-source projects using Web3 technologies.

Team and activities

Cardio Diagnostics Announces Strategic Engagement With Us: Cardio Diagnostics Holdings, Inc (Nasdaq: CDIO), an artificial intelligence-powered precision cardiovascular medicine company, has announced a strategic engagement with Lifespan.io.

Rejuvenation Roundup Podcast

Ryan O’Shea of Future Grind hosts this month’s podcast, showcasing the events and research discussed here.

Journal Club

Reducing DNA Damage With DREAM: In Journal Club this month, we explored a new study published in Nature Structural and Molecular Biology, where researchers demonstrated that by manipulating the DREAM protein complex, a major regulator of DNA damage response, it may be possible to reduce the number of DNA mutations accumulated with age.

Advocacy and Analysis

Bryan Johnson’s Race Against Time: Bryan Johnson is an enigma in the longevity space, someone who is difficult to place in a familiar category or determine the net impact of. Johnson is a successful tech entrepreneur of humble origins who sold his company Braintree Venmo to PayPal in 2013 for 800 million dollars.

What AI Technology Is Doing for Longevity Now: In March 2023, MIT Technology Review revealed that Sam Altman, the CEO of OpenAI (ChatGPT), was the mystery investor behind the $180 million investment into stealth startup Retro Biosciences, a biotech company with the ambition of “adding 10 years to the human lifespan.”

Research Roundup

Cold Temperatures Stimulate Lifespan-Associated Protein: A paper published in Nature Aging describes how cold temperatures stimulate the production of PA28γ, a protein that appears to increase lifespan in worms and cells.

Young Microbiomes in Very Old People: Research published in Nature Aging has illustrated how the gut microbiomes of the longest-lived people are more likely to have bacterial populations associated with youth.

Low Carb Intake Linked to Insulin Resistance: Scientists have published a new study suggesting that low carbohydrate consumption is significantly associated with increased insulin resistance in healthy, lean people.

Reducing Axonal Death and Inflammation in Mouse Brains: Researchers have published a study in Aging Cell on how inhibiting the death of axons in the brain protects the brains of old mice from inflammation.

Air Pollution May Drive Lung Cancer via Inflammation: Researchers have concluded that airborne fine particulate matter, which has been consistently linked to cancer, promotes lung cancer via inflammation and not necessarily via mutagenesis.

Physical Activity, Sleeping, Sedentary Behavior, and Aging: Regular exercise, getting enough sleep, and avoiding sedentary behavior are frequently reported as being important in determining how slowly we age. A team of researchers recently set out to determine the link.

Examining a Factor in the Diabetic Heart: Research published in Heliyon has outlined the effects of F-Klb, a signaling molecule receptor that is released under metabolic stress, on the hearts of diabetic patients. It is the receptor for fibroblast growth factor 21 (FGF21), a regulator of metabolism that is produced both by adipose (fat) cells and the liver.

Age-Related Changes in RNA Transcription Speed: Research published in Nature has described transcriptional elongation changes in the cell with age and how they may be linked to lifespan. Transcriptional elongation is a fundamental biological process that affects the basic steps involved in the production of RNA, which is responsible for executing DNA instructions.

Comparing Mushroom and Animal Protein for Muscle Building: Scientists have reported that protein derived from mushrooms (mycoprotein) has a similar impact on muscle mass and strength as animal-based protein in young, healthy people undergoing resistance training.

Review: Moderate Drinking Doesn’t Lower Mortality: A new comprehensive meta-analysis failed to find any protective effect of moderate drinking on mortality risk. There is an ancient idea that while excessive drinking will kill you, moderate alcohol consumption is actually good for you, and until recently, it seemed to be supported by scientific evidence.

Heart Organoids May Change Future Research: Researchers publishing in Nature Biotechnology have generated epicardioids, which are pluripotent, self-organizing stem cells that allow for better understanding, research, and potentially prevention and treatment of heart disease. The epicardium, a layer of cells surrounding the heart, plays a major role in human embryonic development.

Rapamycin Rescues Age-Impaired Blood Flow in Mice: Scientists have concluded that rapamycin treatment started in early mid-life can prevent age-related blood flow impairment, peripheral artery disease, in the hindlimbs of wild-type, atherosclerotic, and Alzheimer’s model mice.

Amyloid-β Clearance by the Liver Might Help with Alzheimer’s: Chinese scientists have found that the liver removes amyloid-β from circulation in mice, which also decreases its levels in the brain. The age-related impairment of this process might offer a new clue for fighting Alzheimer’s disease.

Case Reports of Sclerotic Fibrosis in the Heart: A pair of case reports published in Heliyon have shed more light on the connection between systemic sclerosis and fatal heart failure, highlighting a need for early diagnosis and treatment.

Uncovering a Predictive Biomarker for Alzheimer’s: Researchers publishing in Alzheimer’s and Dementia have published a correlation between the Alzheimer’s-linked protein tau and another protein, bisecting N-acetylglucosamine (GlcNAc), which suggests its usefulness as a biomarker.

Sleep Quality and Duration Associated with Stroke: Showing yet again that sleep is a serious matter, scientists have reported that short sleep duration, snoring, and long naps are linked to a significantly elevated risk of acute stroke.

Increased Energy Efficiency Might Drive Weight Regain: Scientists have discovered that formerly obese mice that became leaner have greatly improved energy efficiency, which might be preventing their complete return to normal weight.

Examining Cellular Stemness as a Tissue Attribute: In a preprint paper published on bioRxiv, researchers including João Pedro de Magalhães have gotten a glimpse at how stemness declines across tissues with aging.

Reprogramming Fibroblasts in Vivo for Heart Repair: Scientists from Duke University have found a way to make adult fibroblasts differentiate into cardiomyocytes, which might help develop better heart attack treatments.

Simply Being Overweight May Not Be Harmful in Aging: According to a new large-scale populational study, being overweight is not associated with either significant risks or benefits between the ages of 45 and 85. Obesity, however, is a clear risk factor.

Hair Pigment Stem Cells May Work Differently: Researchers publishing in Nature have made the surprising discovery that pigmentation cells (melanocytes) can naturally transition back into the stem cell state in a process called dedifferentiation.

Netrin-1 Rescues Blood Stem Cells in Mice: Scientists have discovered that the protein Netrin-1 alleviates the age-related decline in hematopoietic stem cell function in mice, enhancing HSC transplantation and protecting these mice from the harmful effects of chemotherapy.

Ketone bodies: A double-edged sword for mammalian life span: Endogenous ketogenesis affects mammalian survival, and ketone body supplementation may represent a double-edged sword with respect to survival.

High-Intensity interval training reduces transcriptomic age: A randomized controlled trial: A low dose of HIIT can reduce an mRNA-based measure of biological age in sedentary adults between the ages of 40 and 65 years old. Other changes in gene expression were relatively modest.

Physical activity is associated with slower epigenetic ageing—Findings from the Rhineland study: These findings suggest that regular physical activity slows epigenetic aging by counteracting immunosenescence and lowering cardiovascular risk.

High-Dose Spermidine Supplementation Does Not Increase Spermidine Levels in Blood Plasma and Saliva of Healthy Adults: This study’s results suggest that dietary spermidine is presystemically converted into spermine, which then enters systemic circulation.

Activation of telomerase by TA-65 enhances immunity and reduces inflammation post myocardial infarction: TA-65 increased all major lymphocyte subsets and reduced C-reactive protein in elderly patients 12 months after a heart attack.

Senolytics rejuvenate the reparative activity of human cardiomyocytes and endothelial cells: These results open the path to further studies on using senolytic therapy in age-related cardiac deterioration and rejuvenation.

Engineering longevity—design of a synthetic gene oscillator to slow cellular aging: These results establish a connection between gene network architecture and cellular longevity that could lead to rationally designed gene circuits that slow aging.

AI-Predicted mTOR Inhibitor Reduces Cancer Cell Proliferation and Extends the Lifespan of C. elegans: TKA001 inhibits human cancer cell proliferation in vitro and extends the lifespan of Caenorhabditis elegans, suggesting that TKA001 is able to slow aging in vivo.

Longitudinal associations between use of antihypertensive, antidiabetic, and lipid-lowering medications and biological aging: Calcium channel blockers may decrease biological aging as measured by epigenetic and functional biomarkers.

Vitamin D Supplementation and Its Impact on Mortality and Cardiovascular Outcomes: It appears to lower the risk of all-cause mortality while not showing a decrease in specific cardiovascular morbidity and mortality risk.

News Nuggets

Longevity Prize Announces First Winners: The winners of the Hypothesis Prize have been announced as part of the Longevity Prize initiative. This is an important step for funding rejuvenation research and sets a great precedent for future longevity-focused prizes and open science.

The Maximon Longevity Prize 2023: 50,000 CHF (56,000 USD): Maximon, Europe’s first longevity company builder, is pleased to announce that applications for the Maximon Longevity Prize 2023 are now open. This prestigious prize is awarded to translational longevity research projects that demonstrate exceptional potential to extend human healthspan and lifespan.

Life Biosciences Claims Visual Restoration in Primates: Life Biosciences, a company co-founded by the well-known Dr. David Sinclair, has recently claimed that it has reversed a form of neuropathy in nonhuman primates through gene therapy and epigenetic reprogramming.

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Date Posted: April 28, 2023

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An Opportunity to Support Aging Research with Gitcoin

We have two scientific research projects in the new Gitcoin fundraising round. Help us to combat Alzheimer’s disease or improve how clinical trials are conducted today!

An alternative way to fund science

Gitcoin is a decentralized science (DeSci) platform that utilizes blockchain technology to support the development of open-source projects using Web3 technologies, with the purpose of providing resources to projects that will improve the public good.

The DeSci movement describes a collective of individuals from scientific, independent, building, developing, activist, and organizing backgrounds that collaborate to construct support systems and push for distributed governance to advance scientific discovery.

Lifespan.io is thrilled to participate in this round of funding, and we have two proposals in the current round, demonstrating our dedication to advancing progress in the aging field.

Lifespan.io is developing a therapy for Alzheimer’s

The first of these is the Mindset project, a project to create a light and sound headset that may address Alzheimer’s disease.

Through the generous contributions of approximately $17,000 from previous Gitcoin funding rounds, we have been able to construct an initial hardware and software system. Early tests reveal that it can influence the brain with the light and audio stimulation it produces.

Our system has, so far, generated preclinical data that suggests that neural entrainment, which is when brain activity responds and adjusts to a pattern of external signals such as audio or visual elements, works on humans.

We began the process of developing the Mindset system based on the idea that utilizing entrainment therapy may help reduce the loss of critical connections in the brain, increase cognitive capability, and alleviate the symptoms that typically accompany Alzhemeir’s disease.

This new funding round will help us reach our $50,000 goal, when we will be able to buy the equipment needed to build a cost-effective production prototype. Once we have that, we can then move forward and produce a low cost headset at scale to benefit the greatest number of people possible.

Web3 crowdsourced clinical trials

The second project is the Lifespan.io Web3 program, which has the goal of improving how aging research and clinical trials are funded.

Your contribution can enable us to develop a novel blockchain-based crowdfunding platform. This could provide additional resources for ambitious projects, such as creating treatments to reduce or even reverse the effects of aging.

Existing forms of financing, like grants, have intense competition and are likely to be conservatively invested, so the innovative studies that we are attempting may not receive the money they need. Your assistance can help us create an alternative approach to financing daring, revolutionary initiatives that could be highly impactful.

Need help donating to these projects?

If you are new to the technology, we have made a step-by-step guide on how to donate.

Get a MetaMask wallet.
Acquire $100 (or whatever amount you want) worth of ETH via Coinbase or other methods.
Send this ETH to your MetaMask from Coinbase (or wherever): this could incur a significant gas fee.

Once you have done that, this video (at 4 minutes, 20 seconds) will show you the steps you need to take to donate and ensure that your donation benefits from the matching fund.

Donate today, and help us to make age-related diseases a thing of the past!

Yes I will donate❤️

Date Posted: April 28, 2023

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Netrin-1 Rescues Blood Stem Cells in Mice

Scientists have discovered that the protein Netrin-1 alleviates the age-related decline in hematopoietic stem cell function in mice, enhancing HSC transplantation and protecting these mice from the harmful effects of chemotherapy [1].

(Not) a niche problem

Why We Age: Stem Cell Exhaustion

Stem cell exhaustion is the age-related deficiency of stem cells. This particular hallmark is directly responsible for many of the physical problems associated with aging, such as frailty and a weakened immune system.
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Declining stem cell function (stem cell exhaustion) is linked to numerous aging phenotypes [2]. Stem cells reside in so-called “niches” – microenvironments whose role is to support stem cells’ viability and function. However, stem cell niches themselves are prone to accumulating age-related damage [3].

In this new study, the researchers “sought to determine whether aged blood stem cell function can be restored by rejuvenating their supportive niches within the bone marrow”. The health of hematopoietic stem cells, which give rise to differentiated blood cells, is especially important in the context of blood cancer, with patients often requiring hematopoietic stem cell transplantation (HSCT). HSCT effectiveness diminishes with age, probably due to age-related changes in the bone marrow niche, although the exact mechanisms of this deterioration remain unknown [4].

Target: Netrin-1

The researchers used a mouse model that recapitulates premature aging of the immune system. Transcriptomic analysis revealed multiple genes that were differentially expressed in this model compared to wild-type mice, and the researchers focused on the one that encodes Netrin-1. Since this protein has been linked to angiogenesis (blood vessel building) and osteogenesis (bone building), it seemed plausible that it might be relevant to the BM stem cell niche.

Perusing existing RNA sequencing databases revealed that in bone marrow, Netrin-1 is expressed mostly in mesenchymal stromal cells (MSCs) and epithelial cells (ECs), both of which are important components of the niche. Conditional deletion of Netrin-1 in those cells led to impaired vascular integrity and accumulation of adipocytes (fat cells), both of which are known features of BM niche aging.

More importantly, Netrin-1 deletion seemed to impair stem cell function. In mice with Netrin-1-deficient MSCs, more HSCs were “stuck” in the nonproliferative G0 phase of the cell cycle. This decrease in progenitor activity was accompanied by impaired engraftment capacity when HSCs from Netrin-1-deficient mice were transplanted into wild-type mice. In mice with Netrin-1 knocked down in ECs, similar effects were observed, albeit of a lesser magnitude. An increase in the number of quiescent stem cells and a decline in their engraftment capacity are characteristic of hematopoietic aging.

DNA damage responses restored

The researchers performed RNA sequencing to elucidate the effect of Netrin-1 deletion on gene expression. In MSCs and ECs of Netrin-1-deficient mice, they detected significant upregulation of pathways associated with adipogenesis, cell cycle, and, importantly, DNA damage responses (DDR). Consequently, those cells accumulated more DNA damage than controls.

Accumulation of DNA damage is central to cellular aging. In this experiment, DNA damage was greater in MSCs and ECs taken from aged wild-type mice than those taken from their young counterparts. Strikingly, a two-week Netrin-1 treatment was enough to significantly reverse DNA damage in aged mice. The treatment also resulted in improved bone marrow vascular health.

Protection from chemotherapy-induced damage

However, the important question was whether Netrin-1 supplementation would improve the function of an aged hematopoietic system, which it did. The treatment increased the number of functional HSCs following bone marrow transplantation four-fold. Moreover, HSCs from treated aged mice were almost as fit and competent as those derived from young controls.

The researchers also learned that not all beneficial effects of Netrin-1 supplementation on HSCs result from improvements in the bone marrow niche. Many of those effects were recapitulated when HSCs were co-cultured with Netrin-1 in vitro, showing that Netrin-1 probably exerts its benefits both directly and indirectly, via niche improvements.

Netrin-1 treatment also significantly protected mice from the detrimental effects of chemotherapy. Treated mice demonstrated preservation of body weight and much more robust hematopoietic recovery. When mice were subjected to an especially damaging multiple-dose chemotherapy, the difference in survival was striking, with the treatment group not losing a single mouse:

Conclusion

This study identifies Netrin-1 as a regulator of BM niche health and HSC fitness that at least partially works by restoring DNA damage responses. This discovery might prove important for protecting patients from the harms of chemotherapy and improving HSC transplantation, and it might also apply to the wider context of aging.

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Literature

[1] Ramalingam, P., Gutkin, M. C., Poulos, M. G., Tillery, T., Doughty, C., Winiarski, A., … & Butler, J. M. (2023). Restoring bone marrow niche function rejuvenates aged hematopoietic stem cells by reactivating the DNA Damage Response. Nature Communications, 14(1), 2018.

[2] López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2013). The hallmarks of aging. Cell, 153(6), 1194-1217.

[3] Brunet, A., Goodell, M. A., & Rando, T. A. (2022). Ageing and rejuvenation of tissue stem cells and their niches. Nature Reviews Molecular Cell Biology, 1-18.

[4] Ho, Y. H., & Méndez-Ferrer, S. (2020). Microenvironmental contributions to hematopoietic stem cell aging. Haematologica, 105(1), 38.

Date Posted: April 27, 2023

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Hair Pigment Stem Cells May Work Differently

Researchers publishing in Nature have made the surprising discovery that pigmentation cells (melanocytes) can naturally transition back into the stem cell state in a process called dedifferentiation.

A kinship with hair follicle cells

These researchers begin their study by discussing stem cells and their proliferation. In the common understanding, which appears to be true for blood cells [1], the human body maintains a stem cell population that divides either into identical stem cells or partially differentiated cells that divide into functional, somatic cells [2].

Hair follicle cells have commonalities with melanocytes. When hair regenerates, both follicle stem cells and melanocyte stem cells act, bringing growth and pigmentation to the hair [3]. Melanocyte stem cells are commonly known to occupy a specific niche, and previous work has suggested that this niche becoming depleted is the key cause of hair whitening. We have previously published an interview with this idea in mind.

However, these researchers disagree with the basic essence of that idea, as their results suggest that the stemlike state of hair pigmentation cells can switch back and forth.

The bulge and the hair germ

This research separately examines the bulge and the hair germ, which are known to be the niches associated with hair pigmentation and growth. This research corroborates previous research demonstrating that melanocyte stem cells can sometimes be found in the bulge [4].

However, according to this study’s volumetric analysis, these cells aren’t usually in the bulge at all; instead, they normally reside in the follicle’s hair germ area. When the mature melanocytes are at the part of the hair cycle when they express pigmentation, the stem cells migrate to the bulge and migrate back before the next cycle. This does not occur with hair follicle cells.

No dedicated stem cell niche

The authors developed a fluorescent reporter to track the fate of cells expressing Oca2, which is associated with differentiated, active melanocytes. This is where they confirmed their key discovery: instead of their reporter gene being gradually flushed as the somatic pigmentation cells went away, the gene was being expressed in cells that were displaying more stemlike charcteristics. Therefore, according to this study, these cells had dedifferentiated from a somatic state into a stem cell state.

Furthermore, after repeatedly administering their reporter and checking for the presence of unreported melanocyte stem cells that never became pigment-producing cells, these researchers discovered no such population group. Therefore, they came to a shocking conclusion: there is no truly dedicated niche that contains a reserved population of melanocyte stem cells.

There is also an explanation for how and why melanocytes decline with aging. Using a population of genetically engineered mice, the researchers found that Wnt signaling is crucial to melanocyte stem cell fate. If Wnt is always on, the cells stay differentiated and die off; if Wnt is off, the cells cannot differentiate and hair turns white. This is in accordance with previous research [3].

Conclusion

The researchers note two different downstream consequences of their findings. Cells that regularly transition back into stem cells appear to be rejuvenative at first glance, but this could cause accelerated aging instead, as these transitory cells aren’t able to protect themselves from damage in the way that a dedicated stem cell population can. The second consequence is considerably more dire: this paper offers at least a partial explanation for the aggressiveness of melanoma, which occurs when out-of-control melanocytes become cancerous.

While this is a mouse study and these findings fly in the face of the widely held understanding of the melanocyte stem cell niche, this was a peer-reviewed study published in a major academic journal, and it certainly warrants further investigation. If these researchers’ results are confirmed to be true in human beings, they may offer an entirely new set of approaches to hair graying with age.

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Literature

[1] Seita, J., & Weissman, I. L. (2010). Hematopoietic stem cell: self‐renewal versus differentiation. Wiley Interdisciplinary Reviews: Systems Biology and Medicine, 2(6), 640-653.

[2] Cockburn, K., Annusver, K., Gonzalez, D. G., Ganesan, S., May, D. P., Mesa, K. R., … & Greco, V. (2022). Gradual differentiation uncoupled from cell cycle exit generates heterogeneity in the epidermal stem cell layer. Nature Cell Biology, 1-9.

[3] Rabbani, P., Takeo, M., Chou, W., Myung, P., Bosenberg, M., Chin, L., … & Ito, M. (2011). Coordinated activation of Wnt in epithelial and melanocyte stem cells initiates pigmented hair regeneration. Cell, 145(6), 941-955.

[4] Nishimura, E. K., Jordan, S. A., Oshima, H., Yoshida, H., Osawa, M., Moriyama, M., … & Nishikawa, S. I. (2002). Dominant role of the niche in melanocyte stem-cell fate determination. Nature, 416(6883), 854-860.

Date Posted: April 27, 2023

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Zuzalu: The Experimental Pop-Up City With a Longevity Focus

The decentralized autonomous organization VitaDAO is supporting longevity realated initiatives at Zuzalu, a pop-up mini-city event in Montenegro, which aims to create a unique jurisdiction for medical innovation within a more effective regulatory framework.

A platform for longevity events and workshops

VitaDAO is hosting unique, longevity-oriented events and workshops in Zuzalu which are designed to accommodate 200-300 longevity enthusiasts.

While establishing industry connections, participants will be coming together to explore the possibility of deepening the ecosystem surrounding longevity and solidifying its regulatory structure. There are also health-improving activities available during this long-term event’s health track.

Held between March and May 2023, the mini-city experiment is hosting several workshops and events. The topics will include cryptography, synthetic biology, the concepts of pop-up cities and digital tribes, and multiple facets of the DAO ecosystem and longevity.

Participants have the opportunity to learn about longevity innovations, take part in workshops and initiatives to improve their own longevity, engage in the latest discourse in biotech, and engage in the conference’s primary topic of a new jurisdiction and regulatory framework for longevity.

In addition, the event’s health track takes a holistic approach to health, allowing participants to check their biomarkers while exploring diets and exercise routines designed to help improve health.

The mini-city experiment was created by Vitalik Buterin, founder of Ethereum and an avid supporter of aging and rejuvenation research. The event is being attended by some of the industry’s most well-known figures, such as Aubrey de Grey, President and CSO of the LEV Foundation; Joe Betts-LaCroix, CEO of Retro Biosciences; Nathan S. Cheng of Healthspan Capital; Laurence Ion and Tyler Golato of VitaDAO; and Stephanie Dainow, Lifespan.io’s Executive Director, among many other noteworthy industry names.

Personal connections to decentralized ideas

Driving deeper connections and establishing an environment of learning is at the heart of this pioneering event. The Zuzalu mini-city is meant to be a holistic experience that creates an atmosphere in tune with longevity. Participants have the opportunity to discuss lifespan-related topics and can dive deeper into the ecosystem with health programs, community activities, workshops and hackathons, immersing themselves in the experience. A step away from VitaDAO’s virtual decentralized format, Zuzalu intends to capitalize on human connections over the two months of its existence.

Apply to visit the main Longevity Biotech Conference at Zuzalu in May.

Yes I will donate❤️

Date Posted: April 26, 2023

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What AI Technology Is Doing for Longevity Now

In March 2023, MIT Technology Review revealed that Sam Altman, the CEO of OpenAI (ChatGPT), was the mystery investor behind the $180 million investment into stealth startup Retro Biosciences, a biotech company with the ambition of “adding 10 years to the human lifespan.” This investment marks the latest tech entrepreneur expressing their interest in longevity science and a new connection with innovative AI technology.

According to February 2023 reports, AI is continuing to gain traction in healthcare applications. Currently, the market is estimated at $14.6 billion (USD) with a compound annual growth rate (CAGR) of 47.6%, with solutions spread across various healthcare fields, such as patient data and risk analysis, precision medicine, cybersecurity, lifestyle management, and drug discovery.

AI is currently being used in longevity and healthcare

The increasing convergence of AI technology and longevity science is sparking advancements in the sector, with established businesses, start-ups, and researchers utilizing the technology. Most recently, scientists explored how ChatGPT, an AI-based language model, was able to predict Alzheimer’s in 80% of cases when analyzing speech. However, it is not the only implementation.

Due to its capabilities of analyzing a vast range of data, AI is proving instrumental in the discovery and development of new compounds. One such application is Insilico Medicine’s ChatPandaGPT integration, which allows researchers to ‘talk’ to its PandaOmics target discovery platform, thus analyzing and navigating large datasets in order to discover new biomarkers and therapeutic targets.

Atificial intelligence models are currently being used to conduct genomic analysis and identify specific genes associated with healthy human lifespan. One such project is Calico Labs’ collaboration with the well-known platform AncestryDNA, which analyzes a vast range of data to establish hereditary factors in longevity.

Personalized medicine

By using AI technology, researchers may be better able to detect iomarkers for disease early, facilitating prompt interventions. BioAge Labs’ partnership with Age Labs AS seeks to analyze samples and health records from the Nord-Trøndelag Health Study (HUNT) biobank to develop novel therapeutics.

The precise impact of diet and exercise on the individual level is still not completely understood, and AI may change that by analyzing a wider range of data. Nutrino’s personalized AI platform is a predictive glycemic response algorithm that can help optimize eating habits and potentially reduce diabetes.

On a similar note, pecision medicine allows for tailored medical solutions. AI can be employed to analyze relevant data and help design and deploy these strategies. For example, Deep 6 AI’s clinical trial matching system connects participants, patients, and researchers for clinical trials in order to broaden databases.

Occasionally, AI has been known to spot what a human cannot due to its ability to analyze data more closely and at greater volumes. Zebra Medical Computer Vision AI medical imaging tool can be used to analyze data, including medical imaging, to diagnose diseases, such as bone, liver, lung, and cardiovascular illnesses. This start-up was recently purchased by Nanox for a rumored sum of $200 million.

Using AI in longevity research

Recent advancements in the sector and widespread application across various industries have shown the technology to be effective. Although each AI implementation is different, in longevity, it is finding its application due to its capabilities for analyzing and working with the immense range of data in the healthcare sphere, allowing researchers to identify patterns, relationships, and evaluate factors in age-related diseases. In turn, they are better able to develop potential solutions and test them, at least in the initial stages, to ensure their feasibility.

Despite the achievements, AI isn’t a flawless solution, and people who apply the technology in their work are advised to do so with caution to ensure that any solutions created operate efficiently and can be used responsibly. For example, biased data introduced into AI datasets can discriminate against or favor certain groups. In addition, such models may contain incomplete or inaccurate data, making them ineffective.

For AI in longevity to work effectively, it must have access to expansive datasets. This creates an issue wherein sensitive data could be breached or exposed. In addition, it raises concerns of consent, as people may be unaware of when and how their data is used. These risks could be minimized by the responsible application and security of AI.

Although this isn’t exclusive to AI, the risk of geographical and economic disparities in access, as with most state-of-the-art technology, means that access may be limited. This raises ethical concerns about how datasets are used, whom they are used for, and who will benefit from the solutions. As artificial intelligence technology advances, more benefits and challenges to its usage will become apparent.

Summary

Recent implementations of artificial intelligence in the longevity sector have presented some impressive results, including the power to harness data in order to deliver tangible suggestions for therapeutics development and to analyze medical images. As AI continues to advance, its potential appears to grow in tandem. However, scientists should be careful to avoid data-related ethical concerns and pitfalls when onboarding this new technology.

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Date Posted: April 26, 2023

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Simply Being Overweight May Not Be Harmful in Aging

According to a new large-scale populational study, being overweight is not associated with either significant risks or benefits between the ages of 45 and 85. Obesity, however, is a clear risk factor [1].

BMI plus fat mass index

While obesity is widely recognized as a life-long risk factor, several studies suggest that people who are simply overweight might be at a lower risk of death than their lean counterparts [2], especially at older ages [3]. However, many scientists attribute these results to a failure to account for variables such as body shape and long-term shifts in BMI (body mass index). The debate is far from settled, and this new study provides yet another angle.

The authors used UK Biobank, a vast repository of health data on almost half a million British citizens, to analyze the association between being overweight or obese and the risk of death at various ages, from 45 to 85. To address another common claim, that BMI does not always reflect body composition (muscular people can have high BMIs without actually being obese), the researchers used an additional metric: fat mass index. This is calculated the same way as BMI but using only fat mass.

The researchers adjusted their model for an impressive array of potential confounders, including physical activity, dietary patterns, smoking, history of disease, socioeconomic status, educational attainment, and even salt consumption and leisure-time screen use. The final analysis included about 370,000 people. The participants were categorized by BMI as underweight (under 18.5 kg/m^2), normal weight (18.5–24.9 kg/m^2), overweight (25.0–29.9 kg/m^2), obesity class 1 (30.0–34.9 kg/m^2), and obesity class 2 (at least 35 kg/m^2).

A bit of extra weight seems benign

The results showed that being overweight, both according to BMI and fat mass index, was only moderately associated with mortality risk at any given age. While an inverse association was indeed observed at ages 45 to 55, the statistical power in this age group was considerably lower due to fewer deaths. The graph shows a small bump in mortality risk for overweight people between ages 55 and 75, but this association vanishes according to BMI and is reversed according to fat mass index in older people. The researchers add a caveat to this last observation, saying that “the magnitude of association was small and may not be clinically meaningful”.

The picture was much clearer for obesity, especially extreme obesity, which was highly associated with mortality, even at younger ages. When measured by BMI, the association barely changed across all age groups, and it became only slightly attenuated with age when measured by fat mass index:

The main upshot of the study, according to its authors, is that obesity should be prevented at any age, while the association between being overweight and mortality is more nuanced. The researchers also note that while BMI and fat mass index showed a slightly different picture, those differences were small, and the correlation between the two indices stood at ≥0.93. Hence, BMI can be safely used as a measure of adiposity in future studies.

Surprising high lean mass results

Regarding the attenuation of the relationship between fat mass and mortality in the oldest participants, the researchers suggest a methodological explanation. First, people who reach old age despite their obesity might be genetically well-protected from its harmful effects. Second, at this point, the risk of cancer, cardiovascular diseases and frailty is so high that body composition becomes a relatively less important factor.

Interestingly, the researchers found the group with the highest lean mass (i.e., the most muscle) at a 20% to 30% higher risk of mortality from 55 to 75 years, which is consistent with some previous studies [4]. If these results are accurate, they pose an interesting question of why supposedly fit people with very high lean mass are at an increased risk. According to the researchers, “previous authors have suggested that muscle quality matters more than quantity when it comes to cardiometabolic health, and future research should consider factors such as microvasculature, muscle fiber type distribution and size, fat infiltration, and fat-free mass function.”

Conclusion

By adding stratification by age, this study paints a clearer picture of the relationship between adiposity and mortality risk with aging. According to the results, being overweight neither significantly increases nor decreases mortality risk. Obesity, however, seems to be equally harmful at all ages. While this might be the largest such study to date, it still has all the usual limitations of a populational study and cannot establish causation.

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Literature

[1] Sanchez-Lastra, M. A., Ding, D., Dalene, K. E., del Pozo Cruz, B., Ekelund, U., & Tarp, J. (2023). Body composition and mortality from middle to old age: a prospective cohort study from the UK Biobank. International Journal of Obesity, 1-8.

[2] Flegal, K. M., Kit, B. K., Orpana, H., & Graubard, B. I. (2013). Association of all-cause mortality with overweight and obesity using standard body mass index categories: a systematic review and meta-analysis. Jama, 309(1), 71-82.

[3] Doehner, W., Clark, A., & Anker, S. D. (2010). The obesity paradox: weighing the benefit. European heart journal, 31(2), 146-148.

[4] Lagacé, J. C., Brochu, M., & Dionne, I. J. (2020). A counterintuitive perspective for the role of fat‐free mass in metabolic health. Journal of Cachexia, Sarcopenia and Muscle, 11(2), 343-347.

Date Posted: April 26, 2023

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Life Biosciences Claims Visual Restoration in Primates

Life Biosciences, a company co-founded by the well-known Dr. David Sinclair, has recently claimed that it has reversed a form of neuropathy in nonhuman primates through gene therapy and epigenetic reprogramming. The full press release is included here.

Life Biosciences, a biotechnology company advancing innovative cellular rejuvenation technologies to reverse diseases of aging and injury and ultimately restore health for patients, today announced preclinical data in nonhuman primates (NHP) for its novel gene therapy candidate which uses a partial epigenetic reprogramming approach to restore visual function.

This approach has been shown to reverse aging, improve vision, and extend lifespan in mice, but whether epigenetic reprogramming would work in primates was not known. Today, researchers at Life Bio and academic researchers, including Dr. Bruce Ksander and Dr. David Sinclair, reported that Life Bio’s therapy significantly restored visual function in an NHP model of non-arteritic anterior ischemic optic neuropathy (NAION), a disorder similar to a stroke of the eye that is characterized by painless yet sudden loss of vision. The data, presented at the Association for Research in Vision and Ophthalmology (ARVO) 2023 conference in New Orleans, LA, represents an important step forward toward enabling human clinical trials to potentially treat a variety of ophthalmic disorders and other diseases of aging.

Life Bio’s lead platform reprograms the epigenome of older animals to resemble that of younger animals via expression of three Yamanaka factors, Oct4, Sox2, and Klf4, collectively known as OSK. The approach partially reprograms cells to resemble a more youthful state while retaining their original cellular identity. Previous data from Life Bio and academic researchers, which were also presented at ARVO 2023, have shown that treatment with OSK reverses retinal aging and restores vision in old mice in a mouse model of glaucoma. Now, with the data presented today at ARVO, the company has demonstrated restoration of visual function and increased nerve axon survival in an NHP model that mimics human NAION deficits in retinal ganglion cells. Key data highlights include the following:

Laser-induced damage to the eyes of NHPs showed a reduction in the key ophthalmic measures that are typically seen in humans with NAION, including pattern electroretinogram (pERG) signals, optical coherence tomography (OCT), retinal nerve fiber layer (RNFL) thickness, and number of surviving optic nerve axons.
NHPs received an intravitreal (in-eye) injection of doxycycline-inducible OSK viruses or vehicle one day after laser damage. Doxycycline was administered systemically until the end of the study.
When eyes were treated with OSK after laser damage, OSK significantly restored pERG responses compared to controls, consistent with restoration of vision.
OSK also significantly improved the number of healthy axon bundles compared to controls.

“NAION is the most common cause of acute optic neuropathy in people over 50, but currently has no effective treatment. The data we are presenting here show, for the very first time, that treatment with OSK can lead to significant recovery in affected visual function in an NHP model of NAION, the gold standard translational model. That potential unlocks new opportunities for cellular rejuvenation, not just in NAION but in other ophthalmic diseases that occur as a result of retinal ganglion cell dysfunction as we age,” said Bruce Ksander, PhD, Associate Professor of Ophthalmology and Co-Director of the Ocular Oncology Center of Excellence at Harvard Medical School, and lead presenter of the study at the ARVO conference.

Sharon Rosenzweig-Lipson, PhD, Chief Scientific Officer of Life Bio, added, “We are delighted to present this truly groundbreaking data, which further validate Life Bio’s innovative approach to cellular rejuvenation. This approach has implications far beyond NAION and even the vision field, and we are pleased to share data that support the continued development of our scientific platform to address diseases of aging and restore human health.”

Life Bio is advancing its cellular rejuvenation capabilities across a range of aging-related diseases, including additional ophthalmic and neurodegenerative indications. The data being presented at ARVO builds on previous findings from Dr. David Sinclair’s and Dr. Bruce Ksander’s labs at Harvard Medical School showing that OSK can reverse aging in mice.

Dr. Sinclair, Co-Founder of Life Bio, Member of the company’s Board of Directors, Professor in the Department of Genetics and Co-Director of the Paul F. Glenn Center for Biology of Aging Research at Harvard Medical School, and coauthor on the study, said, “Demonstrating rejuvenation in nonhuman primates is a major step forward in advancing cellular rejuvenation as a way of treating both common and rare diseases in the eye and potentially other tissues. What we’ve learned in NHPs has important ramifications for research on reversing aging and is likely to be highly translational to humans. This data moves us an important step closer to the first clinical trials of how cellular rejuvenation technology could treat aging-related diseases.”

About Life Biosciences

Life Biosciences is a biotechnology company advancing innovative cellular rejuvenation platforms to reverse diseases of aging and injury and ultimately restore health for patients. The company is focusing on two platforms targeting key mechanisms underlying aging biology, epigenetic reprogramming and chaperone-mediated autophagy, to restore cells to a more youthful state. Therapies developed within these platforms have the potential to prevent, treat, and/or reverse multiple aging-related diseases. For more information, please visit lifebiosciences.com or follow us on Twitter and LinkedIn.

About OSK

Life Bio’s lead platform, OSK, was invented in the lab of Professor David Sinclair, AO, PhD, Co-Founder of Life Bio, Member of the company’s Board of Directors, and Professor in the Department of Genetics and Co-Director of the Paul F. Glenn Center for Biology of Aging Research at Harvard Medical School. The partial reprogramming technology was in-licensed by Life Bio from Harvard University. The technology was based on Dr. Sinclair’s Information Theory of Aging and works by reprogramming the epigenome of older animals to resemble that of younger animals via expression of three Yamanaka factors, Oct4, Sox2, and Klf4, collectively known as OSK. The approach partially reprograms cells to resemble a more youthful state while retaining their original cellular identity.

Media Contact

Gwendolyn Schanker

LifeSci Communications

gschanker@lifescicomms.com

Date Posted: April 25, 2023

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Reprogramming Fibroblasts in Vivo for Heart Repair

Scientists from Duke University have found a way to make adult fibroblasts differentiate into cardiomyocytes, which might help develop better heart attack treatments [1].

The imperfect repair

Myocardial infarction, or heart attack, is a leading cause of death and disability. It happens when the blood flow to a part of the heart gets blocked, often by a blood clot, leading to cell death and necrosis [2]. When the blood flow is restored, the healing is similar to that of flesh wounds. Fibroblasts recruited to the area produce a lot of intracellular matrix elements, which results in the formation of stiff scar tissue. This decreases the heart’s efficiency, negatively affecting future lifespan and healthspan.

This imperfect repair process reflects the changes we undergo after birth. Fibroblasts are multipotent cells that can differentiate into other cell types, such as adipocytes, chondrocytes, and cardiomyocytes, the heart muscle cells. This process is effective in fetuses and newborns, which is why cuts on a newborn’s skin often heal perfectly without leaving any scar tissue. However, after a fairly short time, fibroblasts become less inclined to differentiate, preferring to produce the extracellular matrix instead.

Scientists have been looking for ways to trick adult fibroblasts into behaving “immaturely”, differentiating into myocytes to heal myocardial infarction more effectively [3]. However, attempts at direct fibroblasts to myocytes reprogramming in vivo have been hampered by low reprogramming efficiency. Apparently, it’s hard to teach old fibroblasts new tricks.

Back in time

In this new study, the researchers attempted to “identify the changes in fibroblasts after birth and how these changes could be manipulated for therapeutic benefits”. First, they isolated cardiac fibroblasts from neonatal and adult mice. All fibroblasts were identically passaged: that is, they had undergone roughly the same number of divisions, which made them of a similar “cellular age”. The fibroblasts were then transfected with a cocktail of four micro-RNAs (miRNAs) that had been shown by previous research to induce reprogramming of fibroblasts into cardiomyocytes, albeit with low efficacy.

Reprogramming worked well in neonatal, but not adult, fibroblasts. The researchers looked at transcription factors that were expressed differently in those two types of fibroblasts and then made several more attempts at reprogramming, each time adding a siRNA (short interfering RNA) to silence one of the candidate factors. Silencing Epas1, which was highly expressed in adult but not neonatal fibroblasts, seemed to work best, robustly increasing the number of reprogramming events in the culture. Conversely, overexpressing Epas1 in neonatal fibroblasts resulted in them losing their remarkable differentiation capacity.

New myocytes and improved cardiac function

To test their new insights, the researchers inflicted myocardial infarction on mice, and then delivered the reprogramming miRNA combo and the Epas1-blocking siRNA directly into the infarction border zone. Two months after the injury, no new cardiomyocytes appeared in mice that received sham treatment. In mice who received only the reprogramming cocktail, few reprogramming events occurred. However, in the mice that also received Epas1-blocking siRNA, about 20% of resident cardiomyocytes turned out to be former fibroblasts. The treatment also significantly improved cardiac function.

Birth may be the trigger

The authors hypothesized about the event that triggers the expression of Epas1 and moves myofibroblasts towards their adult differentiated phenotype. They suggest that this cue might be oxygen deprivation during birth, since low oxygen levels are known to induce Epas1 expression [4]. The researchers mention that low oxygen levels during birth might also be the stimulus behind cardiomyocyte cell cycle exit (adult cardiomyocytes are largely non-proliferative).

The researchers note that while they chose Epas1, which yielded good results, other transcription factors might be at play as well. Targeting several factors at once might lead to even better outcomes. For RNA delivery, the researchers used exosomes, a type of extracellular vesicles used by cells for communication. This method of delivery was popularized by recent COVID-19 vaccines that use it to deliver their RNA cargo.

Conclusion

Regaining the impressive regenerative abilities that we lose soon after birth might be the key to staving off numerous deadly diseases. This research underscores how pliable cell fate can be, and that we might be able to manipulate it to produce new differentiated cells in environments that normally do not allow this. Direct reprogramming of fibroblasts in vivo can also be used outside of the cardiac context, such as in producing new cartilage.

Yes I will donate❤️

Literature

[1] Sun, H., Pratt, R. E., Dzau, V. J., & Hodgkinson, C. P. (2023). Neonatal and adult cardiac fibroblasts exhibit inherent differences in cardiac regenerative capacity. Journal of Biological Chemistry, 104694.

[2] Ojha, N., & Dhamoon, A. S. (2021). Myocardial infarction. In StatPearls [Internet]. StatPearls Publishing.

[3] Chen, Y., Yang, Z., Zhao, Z. A., & Shen, Z. (2017). Direct reprogramming of fibroblasts into cardiomyocytes. Stem cell research & therapy, 8, 1-8.

[4] Peng, J., Zhang, L., Drysdale, L., & Fong, G. H. (2000). The transcription factor EPAS-1/hypoxia-inducible factor 2α plays an important role in vascular remodeling. Proceedings of the National Academy of Sciences, 97(15), 8386-8391.

Date Posted: April 24, 2023

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Examining Cellular Stemness as a Tissue Attribute

In a preprint paper published on bioRxiv, researchers including João Pedro de Magalhães have gotten a glimpse at how stemness declines across tissues with aging.

Using AI to get a grasp on stemness

Why We Age: Stem Cell Exhaustion

As expected, this paper begins with a discussion of stem cell exhaustion and its downstream consequences. It continues with an elaboration on stemness, the particular biochemistry that stem cells exhibit, which underlies efforts to determine what exactly makes a stem cell a stem cell [1]. These researchers note that, even though stem cell exhaustion is a hallmark of aging, most previous efforts, including machine learning efforts, have attempted to define stemness in the context of cancer [2] rather than aging.

Therefore, this team has put machine learning to work in analyzing the transcriptome, the collection of gene transcriptions that RNA has made from DNA. Taking a total of 17,382 samples from 30 different tissues of people between 20 and 79 years old, the researchers followed the same rigorous path as the cancer researchers did [2], assigning a score to samples based on how much they resembled known stem cells.

Stemness declines differently in different tissues

Some of the findings were more surprising than others. Testicular tissue and blood had the highest stemness scores overall, but brain, muscle, and lung tissue were the next three, with various gut tissues and skin following after that. The brain’s stemness score was especially interesting when compared to nerve tissue, which had one of the lowest scores of the studied tissues.

While the data was fuzzy and the correlation was only determined linearly, this algorithm found that some tissues clearly declined more than others. Lung tissue, which did not show many stemlike properties to begin with according to this study, had its score nearly drop to zero at older ages. The prostate and thyroid declined severely, and gut tissues’ decline was less dramatic. As expected, and with few exceptions between tissues, this stemness score was correlated with a proliferation marker and negatively correlated with cellular senescence.

Interestingly, despite the well-known loss of fertility with aging, stemness scores in both the ovary and uterus rose instead of declined. This particular tissue also has unique behaviors in cellular senescence [3].

It may be that not all stemness is good

The researchers then took a closer look at particular cell types, repurposing data from a previous experiment on leukemia and aging [4] to focus on hemapoietic stem cells, which are responsible for making blood. While the correlation was barely outside the threshold for statistical significance, there was a clear trend towards the entirely unintuitive finding that older cells of this type exhibit more stemlike characteristics than their younger counterparts, which may account for an increased rate of cancer. This is particularly notable when compared to other research showing significant depletion of these stem cells with aging [5], and the researchers state that this finding deserves further investigation.

Conclusion

This was not a particularly large experiment, although it has highlighted potentially valuable areas for future research. As the researchers note, it is on correlation, not causation, and it does not identify individual cells as being stem cells or not. Furthermore, the study did not determine which biochemical facets of stemness as a whole are related to the necessary proliferation of healthy cells and what facets are more oriented towards cancer. All of these particulars will need to be examined to untangle which cells we do, and don’t, want to divide in our bodies.

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Literature

[1] Srivastava, A. K., & Bulte, J. W. (2014). Seeing stem cells at work in vivo. Stem cell reviews and reports, 10, 127-144.

[2] Malta, T. M., Sokolov, A., Gentles, A. J., Burzykowski, T., Poisson, L., Weinstein, J. N., … & Schumacher, S. E. (2018). Machine learning identifies stemness features associated with oncogenic dedifferentiation. Cell, 173(2), 338-354.

[3] Chatsirisupachai, K., Palmer, D., Ferreira, S., & de Magalhães, J. P. (2019). A human tissue‐specific transcriptomic analysis reveals a complex relationship between aging, cancer, and cellular senescence. Aging Cell, 18(6), e13041.

[4] Adelman, E. R., Huang, H. T., Roisman, A., Olsson, A., Colaprico, A., Qin, T., … & Figueroa, M. E. (2019). Aging Human Hematopoietic Stem Cells Manifest Profound Epigenetic Reprogramming of Enhancers That May Predispose to Leukemia Epigenetic Reprogramming in Aging Human HSC. Cancer discovery, 9(8), 1080-1101.

[5] de Haan, G., & Lazare, S. S. (2018). Aging of hematopoietic stem cells. Blood, The Journal of the American Society of Hematology, 131(5), 479-487.

Date Posted: April 24, 2023

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Increased Energy Efficiency Might Drive Weight Regain

Scientists have discovered that formerly obese mice that became leaner have greatly improved energy efficiency, which might be preventing their complete return to normal weight [1].

Why is it so hard to lose the last few pounds?

People attempting to lose weight often feel like their own bodies are fighting them, as shedding additional pounds becomes an uphill battle. These people often become frustrated when they maintain or even regain weight when maintaining previously effective routines.

There is a documented mechanism that protects against weight changes by altering the body’s energy efficiency [2]. One study found that the decline in energy expenditure following weight loss (something that makes additional weight loss harder) stems from increased energy efficiency, specifically in skeletal muscle [3]. However, the exact workings of this mechanism had remained unclear.

Massive increase in OXPHOS efficiency

In this new study, the researchers hypothesized that weight loss improves the efficiency of mitochondrial respiration in skeletal muscle. To investigate this, they took wild-type mice and fed them an obesogenic diet for 10 weeks. Then, the mice in this study group were divided into two subgroups: half of the animals continued to receive their high-fat, high-carbohydrate chow, while the rest were put on a standard diet to induce weight loss.

Over the next 10-12 weeks, the average weight of the mice who had been put back on the standard diet (the weight loss group) declined and then stabilized above the level of the control group that was fed non-obesogenic chow from the start (the lean group). In other words, the mice that gained and then lost weight ended up weighing less on average than the obese mice but more than the mice that never experienced weight gain in the first place.

The researchers found that VO₂, the total volume of consumed oxygen and a commonly used metric of energy expenditure, was much higher in the obese mice than in the two other groups, which would be consistent with their higher weight. However, in the lean and the weight loss groups, VO₂ levels were largely identical despite the weight difference. Since the weight loss group was not less physically active than the lean group, the difference must have been in the metabolic rate.

Changes in VO₂ were not associated with adipose tissue. However, in skeletal muscle, weight loss induced a massive 50% increase in the efficiency of oxidative phosphorylation (OXPHOS), the fundamental process of energy production in cells. OXPHOS occurs in mitochondria and produces large amounts of ATP, the molecule that supplies energy for cells. Basically, the mice that had lost weight now needed much less oxygen to produce the same amount of ATP. OXPHOS efficiency in the other two groups was largely identical.

Lipids, not proteins

Interestingly, this impressive improvement in OXPHOS efficiency was not accompanied by any significant changes to the skeletal muscle mitochondrial proteome. Not a single mitochondrial protein showed statistically different levels in the obese and the weight loss groups. If the ATP-producing machinery remained the same, what did change?

The whole OXPHOS “factory” based on five protein complexes is embedded in the inner mitochondrial membrane, which is built from a familiar lipid bilayer. Unlike with the proteome, there were some differences in the muscle mitochondrial lipidome. The researchers noticed that in the weight loss group, TLCL, a type of lipid, was significantly elevated compared to two other groups. Previous research has linked TLCL to OXPHOS efficiency [4]. Knocking down TAZ, an enzyme crucial for TLCL production, increased energy expenditure (i.e., lowered energy efficiency), protecting the mice from diet-induced obesity.

Conclusion

This study shows that weight loss induces a striking 50% increase in energy efficiency compared to situations of both continuous normal weight and obesity. This means that after having lost weight, someone might need to do 50% more work to burn the same number of calories. While the researchers did identify a potential target for intervention, the road to the clinic might be very long. Meanwhile, just being aware of this phenomenon is valuable information that might prevent frustration for people trying to lose instead of regain weight.

Yes I will donate❤️

Literature

[1] Patrick J Ferrara, Marisa J Lang, Jordan M Johnson, Shinya Watanabe, Kelsey L McLaughlin, J Alan Maschek, Anthony R P Verkerke, Piyarat Siripoksup, Amandine Chaix, James E Cox, Kelsey H Fisher-Wellman, Katsuhiko Funai (2023). Weight loss increases skeletal muscle mitochondrial energy efficiency in obese mice, Life Metabolism

[2] Ravussin, Y., Edwin, E., Gallop, M., Xu, L., Bartolomé, A., Kraakman, M. J., … & Ferrante Jr, A. W. (2018). Evidence for a non-leptin system that defends against weight gain in overfeeding. Cell metabolism, 28(2), 289-299.Chicago

[3] Goldsmith, R., Joanisse, D. R., Gallagher, D., Pavlovich, K., Shamoon, E., Leibel, R. L., & Rosenbaum, M. (2010). Effects of experimental weight perturbation on skeletal muscle work efficiency, fuel utilization, and biochemistry in human subjects. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 298(1), R79-R88.

[4] Prola, A., Blondelle, J., Vandestienne, A., Piquereau, J., Denis, R. G., Guyot, S., … & Pilot-Storck, F. (2021). Cardiolipin content controls mitochondrial coupling and energetic efficiency in muscle. Science Advances, 7(1), eabd6322.

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