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Building a Future Free of Age-Related Disease

Life Biosciences
Date Posted: April 26, 2023
Comments Off on Life Biosciences Claims Visual Restoration in Primates

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

Heart DNA
Date Posted: April 25, 2023
Comments Off on Reprogramming Fibroblasts in Vivo for Heart Repair

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.

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

Dividing cell
Date Posted: April 24, 2023
Comments Off on Examining Cellular Stemness as a Tissue Attribute

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

Dividing cells
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.
Read More

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.

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

Depressed obese
Date Posted: April 24, 2023
Comments Off on Increased Energy Efficiency Might Drive Weight Regain

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.

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

Elderly sleep
Date Posted: April 21, 2023
Comments Off on Sleep Quality and Duration Associated with Stroke

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 [1].

Debilitating and deadly

Stroke, an acute condition in which the blood supply to a part of the brain is interrupted, is one of the most prevalent causes of death worldwide. Stroke is also highly age-related, with its likelihood doubling every 10 years after the age of 55. Moreover, stroke survivors have a significantly higher risk of another stroke and shorter life expectancy. One study found that stroke reduces remaining life expectancy by 20% to 40% and the number of disability-free years by up to 90% [2].

For decades, the effects of sleep quality on health have been largely overlooked. However, in recent years, sleep quality has emerged as one of the most potent moderators of health and possibly lifespan. One meta-analysis found that short sleep duration (less than six hours per day) was associated with a 12% increase in all-cause mortality [3]. According to another study, the incidence of coronary heart disease was linked to short sleep duration, and even more robustly, to impaired sleep quality [4].

Strong association

In this new paper, the researchers analyzed the results of the INTERSTROKE study, which involved 4,496 participants, with 1,799 having experienced an ischemic stroke and 439 an intracerebral haemorrhage; the rest of the participants were age- and sex-matched healthy controls.

The researchers found that various sleep characteristics were significantly correlated with stroke incidence. For example, people with an average night sleep duration of less than five hours were more than three times more likely (odds ratio of 3.15) to experience any kind of stroke than people with the reference sleep duration, which the researchers had set at 7 hours. Interestingly, while the odds ratio for ischemic hemorrhage was 2.64, the odds ratio for intracerebral hemorrhage (ICH) was much higher at 9.15.

The researchers saw a clear U-shaped association, which is consistent with previous research. While too little sleep is a likely cause of health problems, too much sleep is often a symptom of a disease. In this study, people with prolonged sleep duration (more than 9 hours on average) were 2.67 times more likely to experience stroke than the reference group.

Short sleep and snoring are the worst

Napping was positively associated with stroke risk as well, except for short (less than one hour) and planned napping, in which the association did not reach statistical significance. People who often took long, unplanned naps had 2.46 times higher odds of stroke.

Self-reported sleep quality and frequent waking were only mildly associated with stroke, while the symptoms of obstructive sleep apnea (OSA) had a strong association. For simple snoring, the odds ratio was 1.91, snorting had 2.64, and breathing cessation had 2.87. Surprisingly, the odds ratio was in the same ballpark for people who responded “do not know” when asked about the prevalence of those symptoms in their sleep.

The researchers also found a significantly cumulative effect of short sleep duration and snoring, with sleep-deprived snorers being 4.04 times more likely to have a stroke. No significant interaction between sleep duration and other symptoms was detected.

Regional and ethnic differences

Unlike most previous studies into stroke, the INTERSTROKE cohort included people from several countries and of various ethnic backgrounds. The researchers found an intriguing, statistically significant effect of both ethnicity and region. In particular, the association between short sleep duration and stroke was the strongest for South Asian ethnicity and region, and not significant for Chinese ethnicity and China. Age and sex were not found to be important factors.

The model was adjusted for several potential confounders, such as occupation, marital status, alcohol consumption, physical activity, diet quality, body mass index (BMI), stress, depression, and history of diabetes. Interestingly, a previous analysis of INTERSTROKE, published about a month ago, revealed a strong correlation between stroke and depressive symptoms [5].

Conclusion

This study adds to the growing body of evidence showing the importance of sleep quality, which is often sacrificed or overlooked in modern society. Getting a lot of good quality sleep might be just as beneficial for your health as eating healthy or exercising. While this particular research paper is just an association study, serious symptoms such as obstructive sleep apnea should be dealt with as soon as possible.

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

Literature

[1] Mc Carthy, C. E., Yusuf, S., Judge, C., Alvarez-Iglesias, A., Hankey, G. J., Oveisgharan, S., … & O’Donnell, M. (2023). Sleep Patterns and the Risk of Acute Stroke: Results from the INTERSTROKE International Case-Control Study. Neurology.

[2] Bardenheier, B. H., Lin, J., Zhuo, X., Ali, M. K., Thompson, T. J., Cheng, Y. J., & Gregg, E. W. (2016). Compression of disability between two birth cohorts of US adults with diabetes, 1992–2012: a prospective longitudinal analysis. The Lancet Diabetes & Endocrinology, 4(8), 686-694.

[3] Cappuccio, F. P., D’Elia, L., Strazzullo, P., & Miller, M. A. (2010). Sleep duration and all-cause mortality: a systematic review and meta-analysis of prospective studies. Sleep, 33(5), 585-592.

[4] Lao, X. Q., Liu, X., Deng, H. B., Chan, T. C., Ho, K. F., Wang, F., … & Yeoh, E. K. (2018). Sleep quality, sleep duration, and the risk of coronary heart disease: a prospective cohort study with 60,586 adults. Journal of Clinical Sleep Medicine, 14(1), 109-117.

[5] Murphy, R. P., Reddin, C., Rosengren, A., Judge, C., Hankey, G. J., Ferguson, J., … & O’Donnell, M. (2023). Depressive Symptoms and Risk of Acute Stroke: INTERSTROKE Case-Control Study. Neurology.

Alzheimer's biomarker
Date Posted: April 20, 2023
Comments Off on Uncovering a Predictive Biomarker for Alzheimer’s

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.

The need for early prediction

This paper begins with a note that to be effective, Alzheimer’s treatment must begin before irrevocable neurodegeneration has already occurred [1]. Therefore, biomarkers for this destructive disease are necessary for its early diagnosis. Previous research has found that specific forms of tau can be found in blood, making them potentially useful for this purpose [2].

Changes in glycosylated proteins (such as GlcNAc) have been previously reported in Alzheimer’s disease, but this relationship has not been completely elucidated [3]. The researchers claim that they have previously shown that GlcNAc is higher in people with Alzheimer’s disease than people without it [4], which led them to do this research specifically on its potential value as a biomarker.

Interesting findings from a longitudinal cohort

Out of a total of 3363 participants in a wide-ranging Swedish study of people older than 60 years old, 233 people were randomly selected for inclusion. All of them were free from dementia at baseline. For a maximum of 17 years, participants under 78 years old were given follow-up assessments every 6 years and older participants were given these assessments every 3 years; all of these assessments contained medical examinations and neurological tests.

In people who did and did not develop Alzheimer’s disease, GlcNAc and tau were found to be significantly, although loosely correlated, with an r of 0.55 for the group that developed Alzheimer’s and an r of 0.27 for the group that did not. In people with full-blown Alzheimer’s, the correlation was even stronger, at 0.85. In people who were found to have developed Alzheimer’s at the first six-year followup, GlcNAc had remained relatively stable.

Interestingly, people with relatively high or low GlcNAc-to-tau ratios had significantly less chance of developing Alzheimer’s than people in the middle of the curve. At baseline, these groups did not have any other statistically significant differences, including age, sex, or mental state.

This study determined that having an intermediate GlcNAc-to-tau ratio is roughly as dangerous as having the Alzheimer’s-linked allele ApoE4. It also determined that people with both of these characteristics have five times the Alzheimer’s risk of people with neither of these characteristics.

Conclusion

When measured alongside tau, bisecting N-acetylglucosamine appears to be a strong biomarker. However, this study opens up several more questions, such as the physiological reasons behind the middle of a statistical group appearing to be more dangerous than the edges. The researchers note that Alzheimer’s was diagnosed clinically, rather than with biomarkers, which helps prevent circularity (using biomarkers to diagnose biomarkers) but does not define the specific characteristics of these Alzheimer’s patients particularly well. They suggest that more work should be done to determine the role of GlcNAc and its value as a biomarker of Alzheimer’s.

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

Literature

[1] Karran, E., Mercken, M., & Strooper, B. D. (2011). The amyloid cascade hypothesis for Alzheimer’s disease: an appraisal for the development of therapeutics. Nature reviews Drug discovery, 10(9), 698-712.

[2] Karikari, T. K., Pascoal, T. A., Ashton, N. J., Janelidze, S., Benedet, A. L., Rodriguez, J. L., … & Blennow, K. (2020). Blood phosphorylated tau 181 as a biomarker for Alzheimer’s disease: a diagnostic performance and prediction modelling study using data from four prospective cohorts. The Lancet Neurology, 19(5), 422-433.

[3] Gaunitz, S., Tjernberg, L. O., & Schedin-Weiss, S. (2021). What can N-glycomics and N-glycoproteomics of cerebrospinal fluid tell us about Alzheimer disease?. Biomolecules, 11(6), 858.

[4] Nagae, M., Kanagawa, M., Morita-Matsumoto, K., Hanashima, S., Kizuka, Y., Taniguchi, N., & Yamaguchi, Y. (2016). Atomic visualization of a flipped-back conformation of bisected glycans bound to specific lectins. Scientific Reports, 6(1), 22973.

2023 Maximon Longevity Prize
Date Posted: April 20, 2023
Comments Off on The Maximon Longevity Prize 2023: 50,000 CHF (56,000 USD)

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.

Maximon rewards the three winners of the prize with 50,000 CHF (56,000 USD). In addition, Maximon’s ventures Biolytica and Avea are offering exclusive rewards to the prize recipient: a personalized longevity concierge program valued at 20,000 CHF and a one-year subscription for longevity supplements valued at 5,000 CHF, respectively.

The prize is open to any academic/non-profit scientist, innovator, student, or startup founder who has either published their breakthrough research, holds a patent, or is in very advanced stages of research. Applications for the Maximon Longevity Prize 2023 will be accepted until June 30th, 2023.

The projects will be evaluated by a panel of renowned experts in the field of longevity research based on their potential for translational impact. The jury includes Dr. Elisabeth Roider, MD, PhD, MBA, Chief Scientific & Medical Officer at Maximon, Nir Barzilai, Director, Einstein Institute for Aging Research at Albert Einstein College of Medicine, Aubrey de Grey, President and CSO at LEV Foundation, Prof. Dr. Collin Ewald, Assistant Professor at ETH Zurich, Prof. Dr. Evelyne Yehudit Bischof, Associate Professor at Shanghai University of Medicine and Health Sciences, Prof Andrea Maier, MD PhD FRACP, Oon Chiew Seng Professor in Medicine, Healthy Ageing and Dementia Research, Yong Loo Lin School of Medicine, National University of Singapore, Heike Bischoff – Ferrari, Professor of Geriatrics and Aging Research at UZH, Sebastien Thuault, Chief Editor at Nature Aging, James Raaff, Co-Founder and Chief Program Officer at Biolytica AG, and Sophie Chabloz, Co-Founder & CPO at Avea Life.

The winners will be honoured during the Longevity Investors Conference (LIC), which brings together leading scientists and investors, fostering collaboration and innovation in the field of longevity. The conference will take place on September 27-29th at Le Grand Bellevue Hotel in Gstaad, Switzerland.

The Maximon Longevity Prize 2023 is a unique opportunity for researchers to showcase their work and contribute to the advancement of longevity research. Interested applicants are encouraged to submit their applications via the following link: https://www.maximon.com/longevityprize2023

About Maximon

Maximon empowers entrepreneurs to build impactful, science-based and scalable companies providing healthy aging and rejuvenation solutions. As a company builder, Maximon identifies the most promising business opportunities in the field of longevity and builds companies from scratch. Maximon provides proven structures, financing, and a unique and inspiring playground for entrepreneurs to build a longevity venture.

Contacts

Dr. Elisabeth Roider, Chief Scientific & Medical Officer at Maximon

Email: elisabeth@maximon.com Phone: +41 76 587 27 21

Maximon AG

Bahnhofplatz

CH-6300 Zug

Switzerland

www.maximon.com

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The Journal Club is a monthly livestream hosted by Dr. Oliver Medvedik which covers the latest aging research papers.
Date Posted: April 20, 2023
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Journal Club April 2023

In the Journal Club this month, we will be exploring 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. Dr. Oliver Medvedik will be hosting the Journal Club which will be streamed live to the lifespan.io Facebook page at 12:00 Eastern time on April 25th.

You may wish to read our news story ‘Inhibiting DREAM for Enhanced DNA Damage Repair’ on this study as a primer for reading the published paper.

Abstract

The DNA-repair capacity in somatic cells is limited compared with that in germ cells. It has remained unknown whether not only lesion-type-specific, but overall repair capacities could be improved. Here we show that the DREAM repressor complex curbs the DNA-repair capacities in somatic tissues of Caenorhabditis elegans. Mutations in the DREAM complex induce germline-like expression patterns of multiple mechanisms of DNA repair in the soma. Consequently, DREAM mutants confer resistance to a wide range of DNA-damage types during development and aging. Similarly, inhibition of the DREAM complex in human cells boosts DNA-repair gene expression and resistance to distinct DNA-damage types. DREAM inhibition leads to decreased DNA damage and prevents photoreceptor loss in progeroid Ercc1−/− mice. We show that the DREAM complex transcriptionally represses essentially all DNA-repair systems and thus operates as a highly conserved master regulator of the somatic limitation of DNA-repair capacities.

Join the Call

Lifespan Heroes can join us for the livestream using the connection information below:

https://lifespan-io.zoom.us/j/83770864184?pwd=c2J0MU1mZjRiRHdCbm5FNDRGSnpGZz09

Meeting ID: 837 7086 4184

Passcode: 873761

Literature

Bujarrabal-Dueso, A., Sendtner, G., Meyer, D. H., Chatzinikolaou, G., Stratigi, K., Garinis, G. A., & Schumacher, B. (2023). The DREAM complex functions as conserved master regulator of somatic DNA-repair capacities. Nature Structural & Molecular Biology, 1-14.
3D Heart
Date Posted: April 19, 2023
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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.

Cardio Dignostics LLP

Check out Cardio Diagnostics to learn more about their test kits.

A systemic autoimmune disease

Systemic sclerosis was once known as scleroderma, as the most visible signs of this disease are on the skin. However, decades of previous research have conclusively proven that this is a systemic disease, as its effects are found in multiple organ systems, most critically the heart [1]. A form of heart failure affects approximately 15% of patients [2], and they are more likely to suffer from heart inflammation, heart fibrosis, and arterial blockages. According to the authors of these case reports, this leads to frequently fatal heart attacks, and they cite previous research showing that only half of people displayed symptoms of heart disease before a heart attack [3].

These authors also note that, although the exact origins of systemic sclerosis remain unclear, the disease first manifests in the microcirculation, the network of capillaries that deliver blood to cells, and this can be diagnosed through a relatively novel technique called laser speckle contrast analysis [4], which works by detecting differences in blood pressure between various parts of the body [5].

First case report

Before he was admitted to the authors’ hospital due to showing heart attack symptoms, this 45-year-old man had suffered from fever and skin necrosis for three months, along with a three-year history of Raynaud’s phenomenon: reduced blood flow to the extremities. Although this hospital diagnosed him with systemic sclerosis and sent him to intensive care with a panoply of treatments, he died two days later.

As expected, his heart had been severely inflamed and enlarged, with the thickened tissue that is a hallmark of systemic sclerosis. Tuberculosis had taken hold in his lungs, and his right lung had necrotic tissue. The exact cause of death was a wide variety of heart diseases, including inflammation, necrosis, and fibrosis.

Second case report

The 59-year-old woman in this report had skin stiffness of the hand for five years before being admitted to the authors’ hospital, where she was diagnosed with systemic sclerosis, lung fibrosis, infection, and pulmonary hypertension. Therefore, the treatments focused on the lungs and relieved some of the related symptoms.

However, she went into fatal cardiac arrest 10 days later. An autopsy confirmed that her heart had suffered many of the same symptoms as in the first case report, with substantial amounts of fibrosis and inflammation. She had also suffered severe fibrosis of the lungs. These heart and lung issues were determined to be the final causes of death.

Conclusion

Case reports are a morbid topic, but they illustrate the reality of disease, particularly age-related disease, and heart disease is still the leading immediate cause of death in the United States. While systemic sclerosis has been reported in adults of all ages [6], it appears to lead to inflammaging and the acceleration of many processes of aging [7]. Significantly more research will need to be done to determine the origins of systemic sclerosis along with potential cures. However, as these case reports make very clear, early diagnosis of systemic diseases and their potential cardiac issues is highly likely to be beneficial on the individual level.

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

Literature

[1] Bruni, C., & Ross, L. (2021). Cardiac involvement in systemic sclerosis: Getting to the heart of the matter. Best Practice & Research Clinical Rheumatology, 35(3), 101668.

[2] Denton, C. P., & Khanna, D. (2017). Systemic sclerosis. The Lancet, 390(10103), 1685-1699.

[3] Marijon, E., Uy-Evanado, A., Dumas, F., Karam, N., Reinier, K., Teodorescu, C., … & Chugh, S. S. (2016). Warning symptoms are associated with survival from sudden cardiac arrest. Annals of internal medicine, 164(1), 23-29.

[4] Lambrecht, V., Cutolo, M., De Keyser, F., Decuman, S., Ruaro, B., Sulli, A., … & Smith, V. (2016). Reliability of the quantitative assessment of peripheral blood perfusion by laser speckle contrast analysis in a systemic sclerosis cohort. Annals of the Rheumatic Diseases, 75(6), 1263-1264.

[5] Sulli, A., Ruaro, B., & Cutolo, M. (2014). Evaluation of blood perfusion by laser speckle contrast analysis in different areas of hands and face in patients with systemic sclerosis. Annals of the Rheumatic Diseases, 73(11), 2059-2061.

[6] Alba, M. A., Velasco, C., Simeón, C. P., Fonollosa, V., Trapiella, L., Egurbide, M. V., … & Espinosa, G. (2014). Early-versus late-onset systemic sclerosis: differences in clinical presentation and outcome in 1037 patients. Medicine, 93(2).

[7] Shen, C. Y., Lu, C. H., Wu, C. H., Li, K. J., Kuo, Y. M., Hsieh, S. C., & Yu, C. L. (2021). Molecular Basis of Accelerated Aging with Immune Dysfunction-Mediated Inflammation (Inflamm-Aging) in Patients with Systemic Sclerosis. Cells, 10(12), 3402.

Liver
Date Posted: April 19, 2023
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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 [1].

The janitor of the body

Despite the flop-laden history of the amyloid-β-centered approach to Alzheimer’s, there is still a lot of data suggesting that this misfolded protein has a lot to do with the disease’s progression. One hypothesis says that amyloid-β (Aβ) plaques are rather a late symptom rather than a cause of Alzheimer’s, and Aβ clearance should be conducted much earlier.

About 40%-60% of Aβ that originates in the brain is transported to the periphery through the blood-brain barrier and cleared from the body [2]. However, until now, scientists knew little about how this happens. In this new study, the researchers investigated the possible role of the liver, the main junk-clearing organ in the body.

Interestingly, liver disorders, such as fibrosis, NAFLD (non-alcoholic fatty liver disease), cirrhosis [3], and even simply abnormal levels of liver enzymes have been linked to Alzheimer’s disease via multiple biomarkers [4]. Several Alzheimer’s-associated genes are highly expressed in hepatocytes (liver cells) [5].

Out from the blood and the brain

In their first experiment, the scientists joined the circulatory systems of pairs of mice (parabiosis). In these pairs, one mouse was wild-type, and the other one was a transgenic model of Alzheimer’s. The researchers found that the peptides Aβ40 and Aβ42, which were produced by the Alzheimer’s mice, were effectively soaked up by the healthy mice’s livers. When Aβ42 was injected in wild-type mice intravenously, it was cleared by the liver in a few hours.

The researchers then measured levels of Aβ40 and Aβ42 in the hepatic inflow and outflow in rabbits and found that the liver removed 14% of Aβ42 and 9% of Aβ40 on average in a single pass.

Then, in six-month old Alzheimer’s mice, the researchers partially occluded the blood flow to the liver to lower Aβ intake. In those animals, blood levels of Aβ40 and Aβ42 shot up 3- and 7-fold, respectively. Importantly, levels of those molecules in the brain were elevated as well: 1.2- and 1.5-fold, respectively. This shows that impaired Aβ clearance by the liver leads to its accumulation in the brain.

The capacity of the liver to get rid of Aβ declined in aged Alzheimer’s mice as well as in aged wild-type rabbits. As a result, old animals had more Aβ peptides in their blood. The researchers also investigated an 84-strong cohort of cognitively normal humans aged 40-90 and found that plasma Aβ40 and Aβ42 levels increased with aging. However, there was no clear association between hepatic function and either age or plasma Aβ levels.

Receptor overexpression increases clearance

Hepatocytes “ingest” Aβ via receptors, of which LRP-1 is the main one. The researchers found that in mice, LRP-1 levels decreased with age, which might explain the reduced Aβ uptake. Alzheimer’s mice with LRP-1 knocked down exhibited lower levels of Aβ in the liver and higher levels in the blood. Interestingly, they also had 37% more Aβ plaques in the cortex and 43% more in the hippocampus than “regular” Alzheimer’s mice. LRP-1-deficient mice also had higher levels of tau phosphorylation, increased neuroinflammation, and more signs of neuronal degeneration. They exhibited impaired cognitive function, including worse spatial learning and memory consolidation.

On the contrary, overexpressing LRP-1 led resulted in higher Aβ levels in the liver and less Aβ in the blood. Such mice also had lower Aβ levels in the brain, less Aβ plaques, lower tau phosphorylation, neuroinflammation, and neurodegeneration, and improved cognitive function.

Conclusion

This study suggests a mechanism behind a well-known link between hepatic function and cognitive decline. If the hypothesis is true, and impaired clearance of Aβ by the liver is one of the causes of its accumulation in the brain, this opens the door to new anti-Alzheimer’s interventions, which is important given the virtual absence of current ones. We are looking forward to similar studies in humans with larger sample sizes.

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

Literature

[1] Cheng, Y., He, C. Y., Tian, D. Y., Chen, S. H., Ren, J. R., Sun, H. L., … & Wang, Y. J. (2023). Physiological β-amyloid clearance by the liver and its therapeutic potential for Alzheimer’s disease. Acta Neuropathologica, 1-15.

[2] Wang, J., Gu, B. J., Masters, C. L., & Wang, Y. J. (2017). A systemic view of Alzheimer disease—insights from amyloid-β metabolism beyond the brain. Nature reviews neurology, 13(10), 612-623.

[3] Newton, J. L., Hollingsworth, K. G., Taylor, R., El‐Sharkawy, A. M., Khan, Z. U., Pearce, R., … & Jones, D. (2008). Cognitive impairment in primary biliary cirrhosis: symptom impact and potential etiology. Hepatology, 48(2), 541-549.

[4] Nho, K., Kueider-Paisley, A., Ahmad, S., MahmoudianDehkordi, S., Arnold, M., Risacher, S. L., … & Alzheimer Disease Metabolomics Consortium. (2019). Association of altered liver enzymes with Alzheimer disease diagnosis, cognition, neuroimaging measures, and cerebrospinal fluid biomarkers. JAMA network open, 2(7), e197978-e197978.

[5] Jansen, I. E., Savage, J. E., Watanabe, K., Bryois, J., Williams, D. M., Steinberg, S., … & Posthuma, D. (2019). Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer’s disease risk. Nature genetics, 51(3), 404-413.

White mouse
Date Posted: April 18, 2023
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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 in the hindlimbs of wild-type, atherosclerotic, and Alzheimer’s model mice [1].

PAD and aging

Peripheral artery disease (PAD) is defined as reduced blood flow to the lower limbs. Age is a major risk factor for PAD, as the disease affects as many as 25% of people over the age of 55 and 40% of people over the age of 80. PAD is also associated with atherosclerosis, diabetes, hypertension, smoking, and Alzheimer’s disease. PAD can develop into a serious incapacitating condition and even require amputation.

Rapamycin, which is well-known for its effects on aging, has been previously demonstrated to improve cerebral blood flow in murine Alzheimer’s models and peripheral blood flow in murine models of atherosclerosis [2] by inhibiting mTORC1, a protein complex that drives growth but also promotes aging processes. This research group has previously shown that mTORC1 drives age-related cerebrovascular degeneration, decreasing cerebral blood flow in old rats [3].

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Let it flow

This study began with an examination of aged but otherwise healthy wild-type mice. As expected, blood flow was significantly impaired in this group. In this initial experiment, rapamycin supplementation, started at 7 months of age, was found to completely block this age-related effect.

Rapamycin PAD 1

In the second experiment, the researchers used a mouse model of atherosclerosis with impaired production of LDL receptors (LDLR). To induce atherosclerosis, these mice were also fed a high-fat diet. Aged atherosclerotic animals had severely impaired blood flow, showing the converging deleterious effects of aging and the disease. Again, rapamycin treatment was able to significantly protect blood flow, although this time, it was not quite to the level of young, wild-type controls. While the difference between rapamycin-treated mice and controls was not statistically significant, it was nonetheless noticeable.

Rapamycin PAD 2

Finally, in hAPP (amyloid precursor protein) mice, an established murine model of Alzheimer’s disease, the researchers observed a similar pattern: blood flow in aged hAPP mice was severely restricted, but hAPP mice fed with rapamycin were largely protected. Here, too, the treatment with rapamycin did not block the decline in blood flow completely, but the difference between the study group and the wild-type controls did not rise to the level of statistical significance.

Rapamycin PAD 3

In all three cases, the researchers also attempted to increase blood flow by applying menthol-based ointment similar to over-the-counter products. In naturally aged mice, rapamycin treatment worked perfectly, completely preventing the age-related decline in the sensitivity of the vasculature to this treatment. However, in both atherosclerotic and hAPP mice, rapamycin only had partial effects:

Rapamycin PAD 4

This might be explained by the converging effects of each of the diseases (AD and atherosclerosis) and aging on blood flow, with rapamycin only being able to counter the age-related portion.

Yes to NO

Menthol increases blood flow, in part, by stimulating the production of NO (nitric oxide), a potent blood flow modulator. According to previous research, mTORC1 represses NOS (nitric oxide synthase) activation, while rapamycin does the exact opposite [4]. It is worth noting, however, that a recent study produced opposite results [5]. According to the researchers, “rapamycin may improve all NO bioavailability, thus negating one of the central impairments in endothelial cell dysfunction, leading to restored vascular function in both brain and the periphery.”

The researchers note that in addition to rapamycin, other mTORC1-modulating interventions such as dietary restriction and intermittent fasting might improve peripheral blood flow and prevent peripheral artery disease, although this requires additional research.

In conclusion, our studies suggest that, in addition to central vascular impairment in aging and age-associated neurological diseases such as AD and vascular dementia, peripheral vascular decline is mediated by mTOR. Interventions that reduce mTOR activity in the vasculature thus have significant promise to prevent or treat PAD.

Conclusion

This mouse study adds to our understanding of rapamycin’s protective effects in an aging organism. PAD is a serious age-related condition that can contribute to other manifestations of aging by restricting the ability to exercise and socialize. It remains to be seen if rapamycin or other rapamycin-mimicking interventions can be effective when started later in life.

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

Literature

[1] Van Skike, C. E., DeRosa, N., Galvan, V., & Hussong, S. A. (2023). Rapamycin restores peripheral blood flow in aged mice and in mouse models of atherosclerosis and Alzheimer’s disease. GeroScience, 1-10.

[2] Jahrling, J. B., Lin, A. L., DeRosa, N., Hussong, S. A., Van Skike, C. E., Girotti, M., … & Galvan, V. (2018). mTOR drives cerebral blood flow and memory deficits in LDLR−/− mice modeling atherosclerosis and vascular cognitive impairment. Journal of Cerebral Blood Flow & Metabolism, 38(1), 58-74.

[3] Van Skike, C. E., Lin, A. L., Roberts Burbank, R., Halloran, J. J., Hernandez, S. F., Cuvillier, J., … & Galvan, V. (2020). mTOR drives cerebrovascular, synaptic, and cognitive dysfunction in normative aging. Aging Cell, 19(1), e13057.

[4] Lin, A. L., Zheng, W., Halloran, J. J., Burbank, R. R., Hussong, S. A., Hart, M. J., … & Galvan, V. (2013). Chronic rapamycin restores brain vascular integrity and function through NO synthase activation and improves memory in symptomatic mice modeling Alzheimer’s disease. Journal of Cerebral Blood Flow & Metabolism, 33(9), 1412-1421.

[5] Wang, Y., Li, Q., Zhang, Z., Peng, K., Zhang, D. M., Yang, Q., … & Sun, C. (2022). mTOR contributes to endothelium-dependent vasorelaxation by promoting eNOS expression and preventing eNOS uncoupling. Communications biology, 5(1), 726.

Heart representation
Date Posted: April 17, 2023
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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.

A background of heart development

The epicardium, a layer of cells surrounding the heart, plays a major role in human embryonic development. Some of these cells migrate towards the heart, developing into vascular and connective tissue, making them a prime target for potential therapies [1]. Whether or not they develop into muscle cells is still under debate [2].

Organoids are created from human cells for the purposes of research, testing, and potential therapeutic use. Previous work has created human organoids from stem cells that mimic some features of the heart [3], but none of this work has focused on the epicardium and its development. Here, the researchers present organoids that organize themselves into seemingly functional cardiac muscle and epicardial tissue: epicardioids.

From pluripotency to specificity

This study begins with human pluripotent stem cells (hPSCs) that the researchers drove towards an epicardial phenotype through the introduction of a host of signaling factors. This research found retinoic acid to be a critical factor in the differentiation and formation of organoids into epicardial tissue and muscle cells, as organoids grown without this compound were loosely organized and poorly differentiated. Supplementing the nascent epicardioids with vascular endothelial growth factor (VEGF) was sufficient for the development of blood vessels within them. This procedure was effective in four separate hPSC lines.

Gene expression analysis showed that these organoids developed into cells necessary for heart function, including pacemaker cells. These cells had similar gene expression profiles as natural cardiac cells in fetal tissue, although the progression of the epicardioids was much faster. The layering and cellular patterns found in these epicardioids was found to be similar to that of human beings, and they responded similarly to signals, such as the growth and regeneration factor NRP2.

The researchers also found evidence for the first heart field (FHF) and juxtacardiac field (JCF) [4], which are transitional stages between hPSCs and epicardial progenitors. These stages had been previously found in animals, but this research reported that they exist in humans as well.

Potential for research and treatment

The researchers were able to replicate medical problems that occur in human beings. Introducing endothelin-1 into their environment recapitulated signs of ventricular hypertrophy, including fibrosis. Using cells from a patient with Noonan syndrome, a genetic defect that leads to fibrosis, led to that same fibrosis in the resulting epicardioids. This gives researchers a potential workbench for treating such diseases.

Conclusion

At the end of their discussion, the researchers note that this research lends itself to the development of therapies that replace cardiac muscle cells lost to heart attacks, including further research on the regenerative factor NRP2. If epicardioids behave similarly to human tissues, particularly if they are more similar to hearts than mouse models, this may speed research and allow for more rapid development of treatments. However, it is unclear if epicardioids can replicate the myriad problems found in aging. More work will be done to determine if stem cells that form heart tissue can be used to develop therapies or be used as an effective therapy themselves.

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

Literature

[1] Quijada, P., Trembley, M. A., & Small, E. M. (2020). The role of the epicardium during heart development and repair. Circulation research, 126(3), 377-394.

[2] Christoffels, V. M., Grieskamp, T., Norden, J., Mommersteeg, M. T., Rudat, C., & Kispert, A. (2009). Tbx18 and the fate of epicardial progenitors. Nature, 458(7240), E8-E9.

[3] Hofbauer, P., Jahnel, S. M., Papai, N., Giesshammer, M., Deyett, A., Schmidt, C., … & Mendjan, S. (2021). Cardioids reveal self-organizing principles of human cardiogenesis. Cell, 184(12), 3299-3317.

[4] Tyser, R. C., Ibarra-Soria, X., McDole, K., Arcot Jayaram, S., Godwin, J., van den Brand, T. A., … & Srinivas, S. (2021). Characterization of a common progenitor pool of the epicardium and myocardium. Science, 371(6533), eabb2986.

Elderly drinking
Date Posted: April 17, 2023
2 Comments

Review: Moderate Drinking Doesn’t Lower Mortality

A new comprehensive meta-analysis failed to find any protective effect of moderate drinking on mortality risk [1].

Linear or U-shaped?

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. Several populational studies have found a U-shaped relationship between drinking and health, with the smallest risk of mortality being associated with low, but not zero, levels of alcohol consumption [2].

However, many scientists have always suspected that those studies might be misleading and plagued with biases such as “reverse causality”. In this case, zero drinkers are actually former drinkers who quit after developing health problems. As a result, their poor health skews the picture for the whole category of teetotalers [3]. Another type of bias is the “occasional drinker bias”, in which people who drink only on rare occasions are bundled with moderate drinkers, possibly boosting the overall health of this group.

Recent high-quality studies, including Mendelian randomization studies in which scientists use genetic variants associated with the investigated factor, such as variants that affect alcohol metabolism, seem to question the “U-shape” assumption [4]. Unfortunately, interventional trials are scarce, albeit some older ones suggest that even moderate alcohol consumption elevates blood pressure [5]. To summarize, the debate is far from over.

A comprehensive review

This new large-scale review of existing literature updates previous research conducted by the same group. It adds a considerable number of studies that appeared in recent years. The review now encompasses more than 100 studies published between January 1980 and July 2021, and almost five million people, with some studies following the same cohorts for decades.

The researchers categorized and weighed the studies, giving more prominence to those of a better quality. They also reran the analysis using occasional drinkers (less than 1 drink per week) rather than never-drinkers as a reference group and stratified the overall population of the studies by mean age (less than 65 or more than 65) and sex.

No benefits to moderate consumption

The results largely confirmed the hypothesis that moderate drinking does not confer any health benefits. Before adjusting for confounding variables and biases, low-volume drinkers (1.3-24.0 g of ethanol per day) indeed showed the lowest mortality risk of all groups. However, the difference between them and abstainers became insignificant in the fully adjusted model.

Occasional drinkers (0 to 1.3 grams of ethanol per day) also did not fare significantly better than lifetime abstainers. Interestingly, although the risk for moderate drinkers (25 to 44 grams per day) was slightly elevated, this difference also did not reach statistical significance. The only two groups who fared significantly worse than lifetime abstainers were moderate to heavy drinkers (45 to 64 grams per day) and heavy drinkers (65+ grams per day). Their relative mortality risk compared to lifetime abstainers was elevated by 19% and 35%, respectively. Shifting the reference group from lifetime abstainers to occasional drinkers did not significantly change the picture.

Interestingly, former drinkers had 26% more risk of death than lifetime abstainers, suggesting that alcohol-related damage cannot be fully reversed by staying off the bottle. When stratified by age, the younger than 65 cohort showed an even higher risk of death for moderate to heavy and heavy drinkers compared to lifetime abstainers. This can be interpreted as an even clearer sign that alcohol is bad for health (young people are generally healthier, which makes alcohol-induced damage more visible).

The association between alcohol and mortality was more pronounced in women, as female moderate drinkers (25 to 45 grams a day) were also at a significantly greater risk of dying than lifetime abstainers. This might be explained by women’s lower average body mass.

Conclusion

According to this new study, moderate drinking does not confer significant benefits in terms of mortality risk. However, it also does not seem to hurt. While this meta-analysis is comprehensive and prioritizes high-quality research, it does not constitute definitive proof, and we are looking forward to new Mendelian randomization and interventional studies.

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

Literature

[1] Zhao, J., Stockwell, T., Naimi, T., Churchill, S., Clay, J., & Sherk, A. (2023). Association Between Daily Alcohol Intake and Risk of All-Cause Mortality: A Systematic Review and Meta-analyses. JAMA Network Open, 6(3), e236185-e236185.

[2] Fillmore, K. M., Kerr, W. C., Stockwell, T., Chikritzhs, T., & Bostrom, A. (2006). Moderate alcohol use and reduced mortality risk: Systematic error in prospective studies. Addiction Research & Theory, 14(2), 101-132.

[3] Thelle, D. S. (2020). Alcohol and heart health: the need for a randomized controlled trial. European Journal of Preventive Cardiology, 27(18), 1964-1966.

[4] Biddinger, K. J., Emdin, C. A., Haas, M. E., Wang, M., Hindy, G., Ellinor, P. T., … & Aragam, K. G. (2022). Association of habitual alcohol intake with risk of cardiovascular disease. JAMA network open, 5(3), e223849-e223849.

[5] Puddey, I. B., Beilin, L. J., Vandongen, R., & Rouse, I. L. (1985). A randomized controlled trial of the effect of alcohol consumption on blood pressure. Clinical and Experimental Pharmacology & Physiology, 12(3), 257-261.

Edible mushrooms
Date Posted: April 14, 2023
Comments Off on Comparing Mushroom and Animal Protein for Muscle Building

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 [1].

Choosing between animal and non-animal sources

Proteins are essential for muscle building, and strong muscles are important for healthy aging. However, this does not mean that a high-protein diet is beneficial, and proteins from various sources are not the same. While a vegan diet can be protein-rich and some people choose not to consume animal proteins for ethical reasons, several studies have suggested that plant proteins are inferior in terms of digestibility and amino acid content [2]. On the other hand, plant protein consumption has been associated with lower all-cause and cardiovascular mortality [3].

Therefore, the question of whether plant protein can be as effective in muscle building as animal protein deserves an answer. Several studies have contributed to this discussion, showing good results for pea [4] and rice [5] proteins.

No clear winner

In this new trial, young, healthy people were subjected to a vigorous training protocol while fed protein-rich diets. One group received protein from various sources (the omnivorous group), while the other did not consume animal protein; instead, their protein was mostly mycoprotein. The researchers used products made by Quorn Foods, a British company that specializes in mycoprotein-based meat substitutes. The study was sponsored by Quorn, but it was designed, conducted, and supervised by the University of Exeter.

The participants consumed 1.8 g of protein per kilogram of body mass per day, which is about twice the recommended amount. The researchers attempted to make both diets as healthy as possible. In both groups, around 25% of energy was provided by fat, and around 50% came from carbohydrates. The daily meals were also largely identical, except for the primary protein source.

Importantly, the vast majority of the participants were habitual omnivores rather than vegetarians or vegans, meaning that whatever long-term consequences of a plant-based diet for muscle building might be, they did not influence the study.

The participants exercised five times per week for 10 weeks in a program designed to maximize muscle hypertrophy. The researchers assessed parameters such as body mass, lean mass, the rate of protein synthesis in the muscles (MyoPS), the size of the muscle fibers, and strength.

Over the course of the experiment, energy, protein, fat, and carbohydrate intakes did not differ between groups. The one notable exclusion was fiber intake, which was double in the plant-based group compared to the omnivorous group, due to the high fiber content of the mycoprotein source (more fiber in your diet is generally considered healthy).

Most of the results did not differ between the groups. Both the omnivorous and vegan groups seemed to benefit equally from the vigorous exercise and the protein-rich diet, putting on muscle mass and increasing muscle strength. Concurrently, daily MyoPS rates were also largely similar for both groups. In a notable exception, in the vegan group, the percentage of the increase in muscle strength was significantly greater for the incline bench press and borderline greater (P = 0.0526) for the deadlift.

The researchers note that while protein consumption targets were achieved in both groups, it was anecdotally harder for the participants on the vegan diet to consume the required amount of protein. This is consistent with previous research that shows somewhat lower protein consumption by vegans and vegetarians than by omnivores.

The limitations

The study had several important limitations. First, the sample size was small, with about ten people in each group. Second, the study was open-label (as opposed to blind), meaning that both the participants themselves and the researchers knew which diet each participant was on. Finally, the study was free-living: the participants only came to the research center from time to time, eating at home and being allowed to exercise at an external gym. This made it impossible to effectively monitor compliance, which might explain the rather high variability of the results.

Dr. Alistair Monteyne, one of the researchers behind the study, said in a statement:

It is well established that muscle building can be augmented by adhering to a high protein diet. Our study demonstrates that mycoprotein is comparable to animal proteins in terms of its ability to facilitate increases in muscle mass and strength in young adults who are regularly engaging in resistance training.

Conclusion

Despite its limitations, this study lends additional support to the hypothesis that non-animal protein can be just as effective in muscle building as animal-derived protein. It also draws attention to an interesting novel source of protein that might gain more prominence in the coming years.

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

[1] Monteyne, A. J., Coelho, M. O., Murton, A. J., Abdelrahman, D. R., Blackwell, J. R., Koscien, C. P., … & Wall, B. T. (2023). Vegan and Omnivorous High Protein Diets Support Comparable Daily Myofibrillar Protein Synthesis Rates and Skeletal Muscle Hypertrophy in Young Adults. The Journal of Nutrition.

[2] van Vliet, S., Burd, N. A., & van Loon, L. J. (2015). The skeletal muscle anabolic response to plant-versus animal-based protein consumption. The Journal of nutrition, 145(9), 1981-1991.

[3] Naghshi, S., Sadeghi, O., Willett, W. C., & Esmaillzadeh, A. (2020). Dietary intake of total, animal, and plant proteins and risk of all cause, cardiovascular, and cancer mortality: systematic review and dose-response meta-analysis of prospective cohort studies. bmj, 370.

[4] Babault, N., Païzis, C., Deley, G., Guérin-Deremaux, L., Saniez, M. H., Lefranc-Millot, C., & Allaert, F. A. (2015). Pea proteins oral supplementation promotes muscle thickness gains during resistance training: a double-blind, randomized, Placebo-controlled clinical trial vs. Whey protein. Journal of the International Society of Sports Nutrition, 12(1), 3.

[5] Joy, J. M., Lowery, R. P., Wilson, J. M., Purpura, M., De Souza, E. O., Wilson, S., … & Jäger, R. (2013). The effects of 8 weeks of whey or rice protein supplementation on body composition and exercise performance. Nutrition journal, 12(1), 1-7.

Prizes
Date Posted: April 13, 2023
Comments Off on Longevity Prize Announces First Winners

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.

Introducing the Longevity Prize

The Longevity Prize is a decentralized science (DeSci) initiative aiming to accelerate research efforts. This is a series of prizes to honor and accelerate progress in longevity and rejuvenation that has been brought to you by VitaDAO, Foresight Institute, Methuselah Foundation, and lifespan.io.

Longevity Prize

The initiative will be offering a series of prizes focused on aging and longevity research, with each prize encouraging project proposals in key areas within the field. The winners of each prize group will then be awarded funds that have been collectively raised by the community supporting the Longevity Prize.

What is the Hypothesis Prize?

Over a century of all the world’s biological knowledge is available to anyone who takes the time to read the literature. There are cases in which key discoveries are made in the past but forgotten for long periods of time, only to be rediscovered. The Hypothesis Prize aims to resurface such discoveries and research areas, focusing our attention on the most promising directions.

This means that important discoveries that have been left languishing or forgotten have the opportunity to be revisited with a modern touch. It also means that this research can be expanded upon using the advances in technology that have arrived since their initial discovery.

Simply put, there could be many interesting research directions buried in the literature that the Hypothesis Prize could help unearth and get funded.

Announcing the winners of the Hypothesis Prize

Co-founder and inventor of Ethereum, Vitalik Buterin joined the event live from Montenegro and talked about the initiative and other related matters. The Hypothesis Prize winners are as follows:

  • $20,000 1st Prize 
    • Carlos Galicia – University of Southern California / Buck Institute
      • Summary: This article suggests that studying the process of renewal that occurs during the formation of an embryo could be a potential solution for age-related decline. To do this, researchers would need to observe how aging marks in gametes develop over the course of embryogenesis, and explore the techniques used by the embryo to rejuvenate itself. To gain a better understanding, the article proposes the use of deep phenotyping, Single Molecule Real-Time DNA sequencing, and multi-omic data analysis. It also mentions the possible clinical implications of the study’s findings.
  • $5,000 2nd Prize
    • Rakhan Aimbetov – Lead @ LABDAO, Hack-Age
      • Summary: Proposes to explore the as yet unknown ways in which the production of faulty proteins can disrupt the balance of proteostasis and result in age-related diseases. Proteostasis is a mechanism that regulates protein levels within cells to maintain the overall health of the body.
  • $2,000 3rd Prize
    • Shahaf Peleg – Group leader, Leibniz-Institut für Nutztierbiologie
    • Andrew Wojtovich – Associate Professor, University of Rochester Medical Center
      • Summary: This proposal presents a new technique, known as external energy replacement, to reduce the effects of aging in the eye and skin. This approach involves using a specially designed, light-sensitive proton pump called mtON to produce ATP in place of the traditional oxidative phosphorylation process.

lifespan.io President Keith Comito had this to say about this important event:

At lifespan.io, we are thrilled to see the enormous amount of enthusiasm for longevity and rejuvenation biotechnologies reflected in the many submissions for the Hypothesis Prize. Furthermore, we are excited by how the selected research proposals highlight potentially overlooked and novel areas with the ability to push the field forward. Congratulations to the winners!

DeSci is an alternative to traditional research funding sources

Traditional funding sources tend to suffer from a risk aversion problem, in which moonshot, high-risk projects are not funded in favor of safer but typically less ambitious ones.

The Longevity Prize (and the greater DeSci movement) represents a real opportunity for our community, rather than government, public institutions, or universities, to choose the directions of research and support the projects they want.

This prize series aims to:

  • Honor and accelerate progress in longevity and rejuvenation.
  • Encourage novel approaches to turning back the aging clock.
  • Differ from standard prize models by generating a flood of proposals, experiments, and collaborations on undervalued areas.
  • Support a growing longevity ecosystem, connecting peopel who generate proposals for progress with people who want to help execute them, and drive high-trust collaboration toward solving them.

In this way, the Longevity Prize is a great way to fast-track the kinds of rejuvenation research we want to see sooner, rather than later.

We wish to send out congratulations to the winners of the Hypothesis Prize and are looking forward to the Biomarker Assessment Prize coming next, which is focused on biomarkers of aging.

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