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Building a Future Free of Age-Related Disease

Diabetes Heart

Senolytics for Cardiac Regeneration in Diabetics

The latest research published in Diabetes has implicated senescent cardiac stem cells as the link between diabetes and cardiovascular disease [1].

Why does diabetes increase the risk of cardiovascular disease?

Type 2 diabetes mellitus is closely related to aging. Aging is a major risk factor for diabetes, and individuals with diabetes exhibit several characteristics of accelerated aging. For example, diabetic patients show higher levels of systemic inflammation and oxidative stress than non-diabetic patients of the same age [2]. They are also more prone to cardiovascular disease and exhibit impaired tissue regeneration [3].

Senescent cells also accumulate in greater numbers in diabetic patients. Senescence can be induced by a number of mechanisms, including diabetes-related pathways. However, even in the absence of diabetes, senescent cells have been shown to contribute to systemic inflammation, oxidative stress, cardiovascular disease, and impaired tissue regeneration [4].

Because of this, researchers have hypothesized that diabetes-induced cellular senescence may be responsible for the cardiac degeneration affects seen in diabetic patients [5]. A multi-center collaboration based out of Magna Graecia University in Italy has recently found evidence to support this theory, specifically in the stem cells of the heart.

Heart tissue samples from diabetes patients show increased cellular senescence

The researchers used heart tissue samples from 50- to 64-year-old patients with and without type 2 diabetes. Tissue was collected during heart surgery from patients who had recently experienced heart attacks. Tissue from diabetic patients showed higher rates of oxidative stress, reduced telomerase activity and telomere length, and an increase in senescent (p16-positive) cells.

Cardiac stem cells that were isolated and cultured from diabetic patients also had reduced proliferation and capacity to differentiate in vitro. Notably, these cells had higher rates of many senescence and SASP markers compared to the non-diabetic control cells.

Senescence was induced in the non-diabetic control cells by exposing them to conditioned media from the diabetic cells, likely because of the SASP. Senescence was also induced in these cells when cultured in a high-glucose condition, which roughly simulates diabetes.

Lastly, treating the cardiac stem cells from diabetic patients with the senolytics dasatinib and quercetin (D+Q) successfully cleared the senescent cardiac stem cells and improved their ability to proliferate and differentiate in vitro.

Senolytics improve cardiac function in a diabetic mouse model

A model of diabetes was utilized in young mice fed a high-fat diet and given streptozotocin injections. These mice had classic symptoms of diabetes, cardiac dysfunction, and an increased senescent (as measured by p16) cell burden.

Treating these mice with D+Q for four weeks greatly reduced the p16 positive cells and dramatically improved cardiac function by several measures in vivo. Additionally, isolated cardiac stem cells from D+Q treated mice had improved proliferation and differentiation along with a reduced SASP compared to the placebo control.

The main findings emanating from this study are that: i) myocardial tissue of non-aged T2DM patients with ischemic cardiomyopathy is characterized by an exaggerated oxidative stress targeting both cardiomyocytes and cardiac stem/progenitor cells (CSCs); ii) Increased oxidative stress in the myocardium of non-aged T2DM patients associates with an increased number of senescent and dysfunctional T2DM-hCSCs as shown by increased p16INK4a, p53 and p21 expression, reduced telomerase activity and telomere length, reduced proliferation, clonogenesis/spherogenesis and myogenic differentiation; iii) T2DM-hCSCs from non-aged subjects show a senescence-associated secretory phenotype (SASP), as demonstrated by the increased secretion of several SASP factors, including MMP-3, PAI1, IL-6, IL-8, IL-1ß and GM-CSF; iv) a combination of two senolytics, Dasatinib and Quercetin, clear senescent T2DM-hCSCs restoring expansion and myogenic differentiation capacities of the remaining diabetic hCSC pool; v) Diabetic cardiomyopathy in young mice, independently of age and ischemia, causes myocardial cell senescence, affecting CSC regenerative potential, cardiac tissue composition and function; vi) D+Q treatment in vivo removes senescent CSCs and improves cardiac repair, regeneration and function in diabetic mice.

Conclusion 

This study provides a mountain of evidence to suggest that the senescence of cardiac stem cells contributes to heart pathology in diabetic patients. Not only was senescence higher in these cells in diabetic tissue, eliminating senescent cardiac stem cells improved function both in vitro for human cells and in an in vivo mouse model.

By conducting their study on younger patients (those who had heart attacks between the ages of 50 and 64) and using a young mouse model of diabetes, the authors show it is not aging alone that contributes to their findings. Still, there are many cofounding factors that may be at play. It is unlikely to be as simple as diabetes causing senescence, which, in turn, causes cardiac degeneration. This study does not contradict findings from other studies, which suggest that other hallmarks of aging are also involved.

Of course, in vitro studies and mouse models do not always translate to humans, but they are, at this stage, the best research tools available. As senolytic treatments race towards the clinic, it will be exciting to see their potential for treating diabetes-related cardiovascular disease.

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

Literature

[1] Marino, F. et al. Diabetes-induced cellular senescence and senescence-associated secretory phenotype impair cardiac regeneration and function independently of age. Diabetes (2022). https://doi.org/10.2337/db21-0536

[2] Halim, M. and Halim, A. The effects of inflammation, aging and oxidative stress on the pathogenesis of diabetes mellitus (type 2 diabetes). Diabetes Metab Syndr (2019). https://doi.org/10.1016/j.dsx.2019.01.040

[3] Dunlay, S.M. et al. Type 2 Diabetes Mellitus and Heart Failure: A Scientific Statement From the American Heart Association and the Heart Failure Society of America. American Heart Association Heart Failure and Transplantation Committee of the Council on Clinical Cardiology; Council on Cardiovascular and Stroke Nursing and the Heart Failure Society of America. Circulation (2019). https://doi.org/10.1161/cir.0000000000000691

[4] Lewis-McDougall, F.C. et al. Aged-senescent cells contribute to impaired heart regeneration. Aging Cell (2019). https://doi.org/10.1111/acel.12931

[5] Shakeri, H. et al. Cellular senescence links aging and diabetes in cardiovascular disease. Am J Physiol Heart Circ Physiol (2018). https://doi.org/10.1152/ajpheart.00287.2018

Aging DNA

Longevity Allele Slows Immune and Cardiovascular Aging

In a new study, mice transduced with a longevity-associated variant (LAV) of the BPIFB4 gene showed less immunosenescence and healthier vasculature [1].

The importance of having good genes

Longevity-associated alleles prove that aging does not affect everyone equally. On average, centenarians and supercentenarians are more protected from age-related diseases than other people, and this protection is better explained by their genes than by their lifestyle choices; it’s not for nothing that longevity often runs in the family.

Geroscientists have been studying these genetic differences for years (check out our interview with Nir Barzilai, one of the most prominent researchers in this field) and have found many gene variants associated with extreme longevity in humans. If only we could somehow extend the benefits that these variants provide to the rest of the human population!

As it happens, scientists have been slowly inching towards making this dream a reality. In this new study, a group of researchers transferred a longevity-associated variant (LAV) of the BPIFB4 gene to mice using viral vectors and saw it rejuvenate the animals’ immune systems and vasculature.

The longevity-associated enigma

Due to its association with longevity established by population studies, the BPIFB4 gene has been in geroscientists’ crosshairs for a few years now. The exact mechanism of action, and even the function of the protein produced by this gene, are poorly understood, but it is known to participate in the maintenance of the immune and cardiovascular systems. In a 2015 study by the same group, the transduction of this LAV led to the restoration of endothelial function and youthful blood pressure levels in old mice [2]. More recently, the group showed that BPIFB4 levels are associated with the severity of COVID-19 in elderly patients [3].

This time, the researchers decided to take a closer look at the effects of this LAV on the harmful age-related changes to the immune system, mainly the ones relating to cellular senescence. First, they confirmed that in aged mice, more blood immune cells express beta-galactosidase (ß-gal), an established marker of cellular senescence. Two months after the mice had been treated with LAV-carrying viral vectors, the prevalence of senescent immune cells significantly decreased in the blood and bone marrow, though it increased in the spleen. The researchers suggest that since the spleen recycles old blood cells, this actually signals an improved clearance of senescent cells from the circulatory system.

Senescent cells secrete the senescence-associated secretory phenotype (SASP) – a cocktail of mostly harmful molecules. The researchers analyzed the levels of three interleukin-based SASP factors: IL-1α, IL-6, and IL-10. All three were more abundant in the blood of old mice than young mice. LAV treatment led to a significant decrease in the levels of IL-1α. A similar trend for IL-6 was observed, though it did not reach statistical significance. The treatment resulted in an additional increase in IL-10, but this is not necessarily bad: not all SASP components are exclusively harmful, and IL-10 is known for its anti-inflammatory action. The scientists hypothesize that higher levels of IL-10 in treated mice represent a more robust anti-inflammatory response.

Via the SASP, senescent blood cells can drive senescence and dysfunction in solid tissues, including in the vasculature [4]. To learn how this mechanism had been affected by LAV treatment, the researchers analyzed senescence levels in the aortae of young and old mice. As expected, the latter had many more senescent cells in the aorta, but this effect was significantly reversed by the treatment.

NAD+ again?

Since cellular senescence and chronic inflammation have been recently linked to age-related deficit of NAD+, an important nutrient-sensing molecule, the researchers analyzed NAD+ dynamics in their mice. As suspected, NAD+ levels declined with age, but LAV treatment attenuated this decline. In an interesting twist, the researchers added a human dimension to their study by looking at NAD+ levels in a group of long-lived people (under 95 years old). On average, these levels were higher in comparison to old healthy controls aged 65-75. Moreover, carriers of the longevity-associated variant of BPIFB4, both hetero- and homozygous, had even more NAD+ in their blood than non-carriers. This does not necessarily mean that the protective effect of this LAV can be recapitulated in people that do not carry it by simple NAD+ supplementation, but it is a possibility. At the very least, it shows the interconnectedness of various processes of aging.

Conclusion

Longevity-associated variants (LAV) of human genes is an exciting area of geroscience. Their mere existence proves that aging is modifiable, while new gene editing techniques hint at exciting future possibilities to extend the benefits of such variants to people who are not endowed with them from birth. This study demonstrates the plausibility of such an approach in a preclinical model.

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

Literature

[1] Ciaglia, E., Lopardo, V., Montella, F., Carrizzo, A., Di Pietro, P., Malavolta, M., … & Puca, A. A. (2022). Transfer of the longevity-associated variant of BPIFB4 gene rejuvenates immune system and vasculature by a reduction of CD38+ macrophages and NAD+ decline. Cell Death & Disease, 13(1), 1-10.

[2] Villa, F., Carrizzo, A., Spinelli, C. C., Ferrario, A., Malovini, A., Maciag, A., … & Puca, A. A. (2015). Genetic analysis reveals a longevity-associated protein modulating endothelial function and angiogenesis. Circulation research, 117(4), 333-345.

[3] Ciaglia, E., Lopardo, V., Montella, F., Sellitto, C., Manzo, V., De Bellis, E., … & Puca, A. A. (2021). BPIFB4 circulating levels and its prognostic relevance in COVID-19. The Journals of Gerontology: Series A, 76(10), 1775-1783.

[4] Yousefzadeh, M. J., Flores, R. R., Zhu, Y., Schmiechen, Z. C., Brooks, R. W., Trussoni, C. E., … & Niedernhofer, L. J. (2021). An aged immune system drives senescence and ageing of solid organs. Nature, 594(7861), 100-105.

Treasure Map

Mapping the Gene Expression of Senescent Brain Cells

As explained in a paper published in GeroScience, researchers have used spatial transcriptomic analysis to show the inflammatory nodes that are caused by brain cells undergoing senescence.

What is spatial transcriptomic analysis?

Spatial transcription analysis isn’t a full 3D view of an entire brain. Rather, it is based on a series of slides of mouse brain, each of which has tiny segments taken and their mRNA analyzed in order to determine these cells’ gene expression.

By analyzing this transcriptome, the researchers found gene expression profiles that were specific to certain areas of the brain. Many genes are abundantly expressed in the midbrain, others are specific to the olfactory area, which is responsible for smell, and still others are much more abundantly expressed in the hypothalamus, which governs hormone production. Similarly, and very usefully from an epigenetic standpoint, the researchers were able to plot the gene expression differences between 28-month-old mice and 3-month-old mice.

With this information in hand, the researchers set their sights on a very specific marker of cellular senescence: Cdkn2a.

How do aged and young mice differ?

The researchers found that older mice had more than twice the senescent cells in the cerebral cortex, four times as many in the connective white matter fiber tracts, and five times as many in the hypothalamus. The total percentages of senescent cells in older mice generally hovered around 1%.

The researchers mapped out which other genes were associated with Cdkn2a, and they carefully mapped out in detail all of the functions of these genes, which were substantially different by cell type. While the technology they used did not allow for resolution at the individual cellular level, the researchers were able to analyze the senescence-associated secretory phenotype (SASP), showing that each one of these senescent ‘spots’ contained multiple different types of heterogenous senescent cells.

Finally, the researchers investigated the effects of these senescent nodes on neighboring cells. They found that while some immune cells, lymphocytes, were not increasingly activated with increased senescence, other immune cells – the brain macrophages known as microglia – were.

Conclusion

The authors conclude their paper by discussing the known downstream effects of cellular senescence in the brain, a topic that we have covered in more than one article, bringing up even more issues, such as reduced white matter repair [1] and a loss of myelination [2], which harms nerve cells’ ability to send signals. Finally, the researchers conclude by lamenting the lack of single-cell resolution in their spatial transcriptomic analysis technique, which would surely help them gather better results.

This research is certainly interesting from a scientific perspective, and it clearly has translational implications. Researchers engaged in studies that involve senolytics, which kill senescent cells, or senomorphics, which render them no longer senescent, might see great value in this approach. By examining their direct effects on Cdkn2a production in mice, such studies could be better poised to find out what compounds just might alleviate senescence-related cognitive decline in humans.

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

Literature

[1] Miyamoto, N., Pham, L. D. D., Hayakawa, K., Matsuzaki, T., Seo, J. H., Magnain, C., … & Arai, K. (2013). Age-related decline in oligodendrogenesis retards white matter repair in mice. Stroke, 44(9), 2573-2578.

[2] Nicaise, A. M., Wagstaff, L. J., Willis, C. M., Paisie, C., Chandok, H., Robson, P., … & Crocker, S. J. (2019). Cellular senescence in progenitor cells contributes to diminished remyelination potential in progressive multiple sclerosis. Proceedings of the National Academy of Sciences, 116(18), 9030-9039.

Reprogramming

Effective New Method of Cellular Reprogramming Proposed

Scientists have proposed a novel method of cellular reprogramming that is more predictable and effective than traditional methods [1].

Geroscience’s Holy Grail

Cellular reprogramming is a hot topic in geroscience that is being pursued by many academics and companies, including major players such as Google’s Calico along with Altos Labs, which is backed by Jeff Bezos. It is such a coveted prize because, if mastered, it will allow us to rejuvenate and replenish cells of various types, leading to a substantial extension in healthspan and possibly lifespan.

Science has come a long way since the original discovery of cellular reprogramming in the 2000s. Back then, the only known way to reprogram cells was with the OSKM cocktail. Since then, scientists have successfully reprogrammed cells using variations of the original formula and sometimes other, unrelated compounds.

Several different ways to introduce the reprogramming factors have also been tested, including plasmids, protein transduction (transport of pre-produced factors into the cell), and various RNA techniques. Yet, as one review notes, none of these techniques is perfect [2]. Cellular reprogramming, though highly promising, remains a difficult task that is plagued with effectiveness and reproducibility issues.

Choose your targets wisely

In this new study, a group of scientists used CRISPR to make cells produce the reprogramming factors endogenously. CRISPR, a technology invented by two Nobel laureates, Jennifer Doudna and Emmanuele Charpentier, can be described as a molecular machine that can perform edits on a DNA molecule with amazing precision.

The specific version of the CRISPR technology that the researchers used is called CRISPRa, with “a” standing for “activation”. Only a fraction of all genes is expressed in each cell at a given time, and genes that induce pluripotency are silenced in differentiated cells. By activating the promoters of such silenced genes, CRISPRa makes them start producing their proteins again. Attempts to use CRISPRa to target cellular reprogramming factors have already been made [3], but there’s always room for improvement.

CRISPR is just a tool, and one of the most important things is what it is aimed at. The researchers chose two more targets beyond OSKM. The first one, Alu-motif, is the most abundant transposable element in the human genome. This is a stretch of DNA, probably a remnant of an ancient virus, that can still reproduce by inserting itself in various loci in our DNA. Such transposons were thought to be just “junk DNA”, but since then, we have learned that over the course of evolution, many transposons have assumed various roles, both beneficial and harmful.

Alu-motif seems to favor the promoter regions of the genes that participate in embryogenesis. Previous research has shown that activating these regions by targeting Alu-motif improves cellular reprogramming.

The second additional target that the researchers chose was a micro-RNA (miRNA) with the unmemorable designation miR-302/367. Micro-RNAs are coded by DNA loci that are not fully fledged genes but rather reside inside other DNA objects, including genes. Despite their tiny size, miRNAs, like transposons, have a lot of important roles. MiR-302/367 is highly expressed in human embryonic stem cells, and targeting it has also been shown to enhance cellular reprogramming [4].

Smoother and more efficient

Two types of cells were used in the experiments: lymphoblastoids, which are derived from lymphocytes, and fibroblasts. The authors demonstrated that CRISPR-based reprogramming that included targeting OSKM along with Alu-motif and miR-302/367 was proven superior to OSKM-only reprogramming. The resulting induced pluripotent stem cells (iPSCs) were more uniform and formed colonies better. The overall reprogramming efficiency – that is, the percentage of cells transformed to bona fide iPSCs – was greatly improved as well.

Using single-cell mRNA sequencing, the researchers followed what they call the reprogramming trajectories of the cells – that is, they analyzed the transition process at several time points. The trajectories of the cells reprogrammed with the new technology were “smoother” or, in the authors’ own words, more deterministic, while the traditional method produced more artifacts, such as spikes in the levels of one of the transcription factors that could potentially throw the cells off course during the reprogramming.

Interestingly, one of the cell lines that the researchers used originated from fibroblasts sourced from an 83-year-old person. Cells of this line have been notoriously hard to reprogram, but the new method passed this exam with flying colors.

Conclusion

Cellular reprogramming has come a long way since Yamanaka’s first experiments. Numerous methods have been introduced, and every new paper extends our understanding of this intricate process. Whether it involves full conversion to iPSCs or cellular rejuvenation without dedifferentiation, cellular reprogramming holds one of the greatest promises in geroscience.

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

Literature

[1] Sokka, J., Yoshihara, M., Kvist, J., Laiho, L., Warren, A., Stadelmann, C., … & Trokovic, R. (2022). CRISPR activation enables high-fidelity reprogramming into human pluripotent stem cells. Stem Cell Reports.

[2] Hu, K. (2014). All roads lead to induced pluripotent stem cells: the technologies of iPSC generation. Stem cells and development, 23(12), 1285-1300.

[3] Weltner, J., Balboa, D., Katayama, S., Bespalov, M., Krjutškov, K., Jouhilahti, E. M., … & Otonkoski, T. (2018). Human pluripotent reprogramming with CRISPR activators. Nature communications, 9(1), 1-12.

[4] Anokye-Danso, F., Trivedi, C. M., Juhr, D., Gupta, M., Cui, Z., Tian, Y., … & Morrisey, E. E. (2011). Highly efficient miRNA-mediated reprogramming of mouse and human somatic cells to pluripotency. Cell stem cell, 8(4), 376-388.

Naked mole rat

Naked Mole Rats Age, but Not Like Other Mammals

A research paper published in Nature by Dr. Vadim Gladyshev and his team has investigated the epigenetic aging of the naked mole rat, an animal whose mortality rate does not appear to increase with age.

Do naked mole rats actually age?

In this paper, the researchers address the question of whether the naked mole rat is truly a negligibly senescent animal: one that does not age. While naked mole rats remain largely youthful in phenotype even after decades of life, with mortality rate remaining steady over the animal’s lifespan [1], its skin becomes more parchment-like and its activity decreases [2], suggesting that aging is having at least some physical effect.

In this study, the researchers used 107 blood samples taken from naked mole rats from newborns to nearly 12 years of age, analyzing their cells for the epigenetic alterations that characterize aging. They found that these animals do age epigenetically, but the way in which they age is unlike that of other rodents.

Two genes make a big difference

The researchers found two genes whose methylation patterns are different between naked mole rats and mice.

One of these genes was telomerase reverse transcriptase (Tert), which is responsible for lengthening telomeres, which erode as cells divide. Telomere attrition is one of the hallmarks of aging, and a lack of Tert would, logically, lead to an increase in this attrition. The researchers found that Tert methylation in the naked mole rat has more methylation sites and gradually increasing methylation with age, which occurs in a different and wider pattern than that of mice.

Naked mole rats have surprisingly short telomeres compared to mice [3]; however, unlike mice (and people), the telomeres of naked mole rats are known to elongate, rather than shorten, over 20 years [4]. This is entirely expected, as the actual gene expression of Tert remains stable over the animal’s lifespan [5].

The steady expression and positive downstream effects of Tert in the naked mole rat seem to be contradictory to its increased methylation with age. However, these researchers suggest that this increased methylation is part of why these animals very rarely get cancer. Somehow, naked mole rats are able to prevent telomere attrition in healthy cells while simultaneously preventing out-of-control cellular division.

The other gene that the researchers found was Prpf19, which was similar to Tert in that its methylation increased more with age, and in a different pattern, than that of mice. This gene is involved in the double-strand break repair of DNA, which is a critical part of maintaining genomic stability.

Conclusion

Epigenetic alterations in the absence of increased mortality are more than just an intellectual curiosity. The evidence presented by these researchers suggests that the processes of aging that occur in naked mole rats are critically and fundamentally different from those of other species.

This research also demonstrates that not all epigenetic alterations are equivalent. Methylation of a few key genes responsible for aspects of cellular maintenance might be linked to multiple downstream diseases of aging. On the other hand, methylation of other genes might also be protective against other diseases of aging in human beings, just as it is in naked mole rats.

One thing, however, is very clear: if we are ever going to harness the naked mole rat’s apparent negligible senescence for ourselves, we must first have a deep and thorough understanding of the biology involved.

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

Literature

[1] Ruby, J. G., Smith, M., & Buffenstein, R. (2018). Naked mole-rat mortality rates defy Gompertzian laws by not increasing with age. elife, 7, e31157.

[2] Buffenstein, R. (2005). The naked mole-rat: a new long-living model for human aging research. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 60(11), 1369-1377.

[3] Tian, X., Doerig, K., Park, R., Can Ran Qin, A., Hwang, C., Neary, A., … & Gorbunova, V. (2018). Evolution of telomere maintenance and tumour suppressor mechanisms across mammals. Philosophical Transactions of the Royal Society B: Biological Sciences, 373(1741), 20160443.

[4] Adwan Shekhidem, H., Sharvit, L., Leman, E., Manov, I., Roichman, A., Holtze, S., … & Atzmon, G. (2019). Telomeres and longevity: a cause or an effect?. International Journal of Molecular Sciences, 20(13), 3233.

[5] Kim, E. B., Fang, X., Fushan, A. A., Huang, Z., Lobanov, A. V., Han, L., … & Gladyshev, V. N. (2011). Genome sequencing reveals insights into physiology and longevity of the naked mole rat. Nature, 479(7372), 223-227.

Food DNA

Higher Diet Quality Is Linked to Reduced Epigenetic Aging

A study published in the American Journal of Clinical Nutrition examined the relationship between diet quality and epigenetic aging clocks [1].

This study used data from the Framingham Heart Study Offspring Cohort. This specific study noted the Dietary Approaches to Stop Hypertension (DASH) scores, which are derived from a food frequency questionnaire (FFQ), of 1,995 people with an average age of 67 years. The researchers also calculated a Mediterranean-style diet score (MDS) and used the Alternate Healthy Eating Index (AHEI).

DNA methylation status was described in a prior study [2]. For participants who attended the eight-exam visit during 2005 and 2008, DNA was extracted from blood samples, and CpG methylation was assigned a value based on a proportion of methylation intensity. During this visit, participants completed an FFQ detailing their intake of each food item in the past year.

Epigenetic age acceleration was measured with the GrimAge [3], Phenoage [4], and DunedinPACE [5] clocks. Higher DASH scores indicate better diets [6,7], and these scores are based on a higher intake of vegetables, fruit, nuts and legumes, whole grains, low-fat dairy along with a lower intake of red and processed meat, sugar-sweetened beverages, and sodium.

Women had higher DASH scores

Participants with higher DASH scores were more likely to be women, had lower BMIs, had higher HDL cholesterol, were less likely to be current or past smokers, and were less likely to be on hypertension medication. The MDS and AHEI scores are extensively featured in the supplementary data, and both of these scores were found to be moderately and significantly correlated with the DASH score.

Higher DASH scores were correlated with decreased epigenetic age acceleration

After adjusting for age, sex, smoking status, physical activity score, BMI, and alcohol consumption, a higher DASH score was associated with less epigenetic age acceleration. For every standard deviation of increase in DASH score, DunedinPACE was decreased by 0.05, GrimAge was decreased by 0.09 and Phenoage was decreased by  0.07.

DASH score and smoking

The researchers conducted another set of analyses using a Bonferroni-corrected P-value threshold of 0.01. These results revealed significant interactions between DASH score and smoking status in their association with DunedinPACE and GrimAge; however, no significant interaction was found between diet quality, age, sex, BMI, and physical activity.

More specifically, the association between the DASH score and epigenetic age acceleration was stronger in the former and current smokers than the never-smokers. This result translates to the never-smokers having lower age acceleration and higher quality diet than the current smokers and former smokers.

Slower epigenetic aging is associated with a higher DASH score

When the researchers analyzed individual DASH components, higher intakes of vegetables, fruit, nuts and legumes, and whole grains were associated with a lower GrimAge. Higher intakes of sodium along with red and processed meat were associated with a higher GrimAge. A lower DunedinPACE and Phenoage were correlated with a higher intake of nuts and legumes.

These analyses also observed a more significant association between DASH score components and epigenetic age acceleration in participants with a history of smoking than in never-smokers. Additionally, in participants with a smoking history, 8 components of the DASH score were associated with GrimAge and 5 components were associated with DunedinPACE, whereas only 1 component was associated with GrimAge in never-smokers.

The investigators ran a sensitivity analysis including the blood cell counts of CD8+ cells, CD4+ T cells, natural killer cells, B cells and granulocytes. These measurements had a statistically significant correlation with DASH scores, MDS, and AHEI.

Finally, DASH scores and increased epigenetic age acceleration were significantly associated with increased all-cause mortality.

Conclusion

These results originate from one food frequency questionnaire that was given at one time point. People cannot always estimate how much food they ate in certain categories in the past year, especially since many people in the United States have varying diets by season. Additionally, the authors noted that this sample consisted of white middle-aged and older adults, so these results can not be generalized to other populations. They concluded with the statement:

Our findings demonstrate that better diet quality was associated with decelerated biological aging, providing a promising avenue to explore the beneficial effects of diet on prolonged lifespans. This effect seems to be more prominent for those who have a history of smoking. Further studies are warranted to validate our findings, including studies with larger sample sizes, studies with racially and ethnically diverse populations, and studies investigating the causal role of dietary factors on epigenetic regulations.

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

Literature

[1] Kim, Y., Huan, T., Joehanes, R., McKeown, N. M., Horvath, S., Levy, D., & Ma, J. (2022). Higher diet quality relates to decelerated epigenetic aging. The American journal of clinical nutrition, 115(1), 163–170. https://doi.org/10.1093/ajcn/nqab201

[2] Huan, T., Joehanes, R., Song, C., Peng, F., Guo, Y., Mendelson, M., Yao, C., Liu, C., Ma, J., Richard, M., Agha, G., Guan, W., Almli, L. M., Conneely, K. N., Keefe, J., Hwang, S. J., Johnson, A. D., Fornage, M., Liang, L., & Levy, D. (2019). Genome-wide identification of DNA methylation QTLs in whole blood highlights pathways for cardiovascular disease. Nature communications, 10(1), 4267. https://doi.org/10.1038/s41467-019-12228-z

[3] Lu, A. T., Quach, A., Wilson, J. G., Reiner, A. P., Aviv, A., Raj, K., Hou, L., Baccarelli, A. A., Li, Y., Stewart, J. D., Whitsel, E. A., Assimes, T. L., Ferrucci, L., & Horvath, S. (2019). DNA methylation GrimAge strongly predicts lifespan and healthspan. Aging, 11(2), 303–327. https://doi.org/10.18632/aging.101684

[4] Levine, M. E., Lu, A. T., Quach, A., Chen, B. H., Assimes, T. L., Bandinelli, S., Hou, L., Baccarelli, A. A., Stewart, J. D., Li, Y., Whitsel, E. A., Wilson, J. G., Reiner, A. P., Aviv, A., Lohman, K., Liu, Y., Ferrucci, L., & Horvath, S. (2018). An epigenetic biomarker of aging for lifespan and healthspan. Aging, 10(4), 573–591. https://doi.org/10.18632/aging.101414

[5] Belsky, D. W., Caspi, A., Arseneault, L., Baccarelli, A., Corcoran, D. L., Gao, X., Hannon, E., Harrington, H. L., Rasmussen, L. J., Houts, R., Huffman, K., Kraus, W. E., Kwon, D., Mill, J., Pieper, C. F., Prinz, J. A., Poulton, R., Schwartz, J., Sugden, K., Vokonas, P., … Moffitt, T. E. (2020). Quantification of the pace of biological aging in humans through a blood test, the DunedinPoAm DNA methylation algorithm. eLife, 9, e54870. https://doi.org/10.7554/eLife.54870

[6] Djoussé, L., Ho, Y. L., Nguyen, X. T., Gagnon, D. R., Wilson, P., Cho, K., Gaziano, J. M., & VA Million Veteran Program (2018). DASH Score and Subsequent Risk of Coronary Artery Disease: The Findings From Million Veteran Program. Journal of the American Heart Association, 7(9), e008089. https://doi.org/10.1161/JAHA.117.008089

[7] Fung, T. T., Chiuve, S. E., McCullough, M. L., Rexrode, K. M., Logroscino, G., & Hu, F. B. (2008). Adherence to a DASH-style diet and risk of coronary heart disease and stroke in women. Archives of internal medicine, 168(7), 713–720. https://doi.org/10.1001/archinte.168.7.713

Mouse clock

Brain Cell Types Respond Differently to Aging Interventions

A new preprint on bioRxiv shows how researchers have developed transcriptomic, cell type specific aging clocks from the regenerative zones of mouse brains [1].

Measuring age at the level of a single cell

Aging is multi-faceted and difficult to quantify. While chronological age is straightforward, it doesn’t necessarily capture the underlying biology, as individuals naturally age at different rates. Additionally, various lifestyle factors and interventions can affect the rate of biological aging; for example, smoking can speed it up and exercise can slow it down.

Machine learning is being utilized to estimate biological age in order to better understand aging, predict remaining healthspan and lifespan, and more efficiently test longevity interventions. These “clocks” can have a variety of different inputs. Most commonly, DNA methylation patterns are used, but newer clocks have incorporated transcriptomics, proteomics, and lifestyle factors, among others.

The source of the biological material is also a major consideration when developing these clocks. Most commonly, bulk tissue is used, averaging measurements from many cells from a specific species and tissue. Recent advancements in technology now allow for these measurements to be made at the single-cell level [2].

This high-resolution approach has opened the door to many questions that were difficult or impossible to answer previously, but it has not yet been used to investigate the aging of different cell types. Do different types age at different rates? Which types are the most useful for predicting chronological and biological age? How do various interventions impact the biological age of different cell types?

A research team based out of Stanford University has used this technology to investigate these cell type-specific contributions to aging in the subventricular zone (SVZ) in mice [1].

The SVZ is regenerative and contains many cell types

The SVZ is a brain region located on the outer wall of the lateral ventricles. It is home to proliferating neural stem cells and is one of the only known sites of neurogenesis in the adult mammalian brain. Because of this important role, its aging progression in mice has been well studied by previous research [3].

In this study, single cell RNAseq was performed on the SVZs of 28 different mice ranging from 3 to 29 months of age. 11 distinct cell types were identified based on each cell’s transcriptome. In particular, oligodendrocytes, microglia, endothelial cells, astrocytes/quiescent neural stem cells (which clustered together), activated neural stem cells/neural progenitor cells (which also clustered together), and neuroblasts were the most abundant. The researchers detected a decline in proliferating neural stem cells with age, validating previous findings regarding the aging SVZ.

Predicting chronological age with the transcriptome of SVZ cells

Next, models were built from this data to predict the chronological age of these mice using the six most abundant cell types. First, these models were built with three cohorts of mice and validated on a fourth. Each cell type had a correlation coefficient (r) between 0.71 and 0.92 with an error between 1.6 and 5.4 months. Bulk models were also created with the same dataset by pooling the single-cell data by cell type. For each cell type, the single-cell models outperformed the bulk models. Their models were also validated and performed well on external datasets from two other studies [4,5].

As a part of the training process for these clocks, the most predictive genes were identified and weighted based on their relative contributions. The researchers’ analyses were able to single out the most important genes and biochemical pathways for each cell type. Most genes and pathways were cell type specific, but others such as AC149090.1 and Ifi27 were key in all or most cell types. This finding shows some ways in which cell types age differently and highlights the value of single-cell analysis relative to bulk tissue methods.

Predicting biological age

The primary function of the SVZ is to maintain proliferating neural stem cells, a capacity that declines markedly with age. This functional capacity was quantified in the neural stem cells, neural progenitor cells, and neuroblasts by measuring the percentage of cells which were in a proliferative cell cycle phase (G2/M and S). Proliferating cells ranged from 5 to 30% of the cell population, depending on the age of the mouse and the cell type. As expected, proliferative fraction was negatively correlated with age (r = -0.8).

This proliferative fraction value was used to train new clocks using similar methods as the chronological age clocks. The biological aging clocks were not as correlated or as accurate at predicting biological age as the chronological aging clocks were at predicting chronological age. However, they still had admirable performance with correlation coefficients between 0.41 and 0.89 and errors between 2.3 to 4.6 months for each cell type. They also performed well on the two external datasets.

Cell type-specific effects of heterochronic parabiosis on chronological and biological age

The researchers used their chronological age and biological age clocks to investigate interventions known to improve age-related decline. First, heterochronic parabiosis (where blood is shared between young and old animals) was conducted on 18 mice.

Exposure to young blood especially rejuvenated the activated neural stem cells/neural progenitor cells. This population had an average chronological age prediction of 4.5 months younger and a  biological age prediction of 2.5 months younger. Other cell types trended towards rejuvenation but to lesser extents. Meanwhile, young mice exposed to old blood were predicted to be older across cell types, especially by the chronological aging clocks.

Exercise also has cell type-specific effects on chronological and biological age

Exercise has many well-characterized, beneficial effects on aging. The researchers used young and old mice with or without running wheels for 5 weeks for these experiments (n=15 total). Oligodendrocytes had their chronological age reduced by 1.4 months in young mice and 2.0 months in old mice and their biological age reduced by 0.6 months in young mice and 0.8 months in old mice. Activated neural stem cells/neural progenitor cells also experienced some rejuvenation (chronological: 1.9 months in young, 0.3 months in old; biological: 1.4 months in young, 1.2 month in old).

For each cell type, heterochronic parabiosis had a larger benefit than exercise. Since activated neural stem cells/neural progenitor cells responded to both interventions, they were used to compare between the two. There was minimal overlap between the transcriptome of these two interventions. This suggests that, despite both interventions targeting aging in a specific cell type, their effects were brought on by largely different mechanisms.

We generated 21,458 single-cell transcriptomes from the neurogenic regions of 28 mice, tiling ages from young to old. With these data, we trained a suite of single cell-based regression models (aging clocks) to predict both chronological age (passage of time) and biological age (fitness, in this case the proliferative capacity of the neurogenic region). Both types of clocks perform well on independent cohorts of mice. Genes underlying the single cell-based aging clocks are mostly cell-type specific, but also include a few shared genes in the interferon and lipid metabolism pathways. We used these single cell-based aging clocks to measure transcriptomic rejuvenation, by generating single cell RNA-seq datasets of SVZ neurogenic regions for two interventions – heterochronic parabiosis (young blood) and exercise. Interestingly, the use of aging clocks reveals that both heterochronic parabiosis and exercise reverse transcriptomic aging in the niche, but in different ways across cell types and genes.

Conclusion

This study is the first to use single cell transcriptome analyses to develop aging clocks. It is full of useful information to longevity researchers, particularly the datasets on aging, heterochronic parabiosis, and exercise in the SVZ. These three datasets should be useful for future research into the genes and pathways involved in both aging and rejuvenation.

This single-cell, high resolution approach highlighted many key findings that are typically washed out in the noise of bulk tissue analysis. In particular, the researchers showed throughout the study that the effects of aging, heterochronic parabiosis, and exercise were cell type-specific: aging looked different depending on which cell type in the SVZ was being evaluated. Additionally, the interventions did not uniformly rejuvenate all cell types. The heterogeneity between cell types is an added layer of complexity with which  longevity researchers will need to continue grappling.

The study’s measure of biological age, proliferative fraction, was less predictive than chronological age. Additionally, it showed smaller changes than chronological age in response to the two interventions. Proliferative fraction is certainly an age-related functional outcome, especially in the SVZ, but it only captures a small piece of biological aging. Ultimately, better outcome measurements are still needed to quantify biological age and to train aging clocks.

Finally, it must be noted that, while exciting, these results are from a pre-print article. This means that they have only been scrutinized by the authors of the paper and have not yet undergone peer review. Additional, clarifying experiments or changes to the interpretation of results may be required before this data is published in a scientific journal.

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

Literature

[1] Buckley, et al. Cell type-specific aging clocks to quantify aging and rejuvenation the regenerative regions of the brain. bioRxiv pre-print (2022). https://doi.org/10.1101/2022.01.10.475747

[2] Singh, S.P. et al. Machine learning based classification of cells into chronological stages using single-cell transcriptomics. Scientific Reports (2018). https://doi.org/10.1038/s41598-018-35218-5

[3] Navarro Negredo, P., Yeo, R.W. & Brunet, A. Aging and Rejuvenation of Neural Stem Cells and Their Niches. Cell Stem Cell (2020). https://doi.org/10.1016/j.stem.2020.07.002

[4] Dulken, B.W. et al. Single-cell analysis reveals T cell infiltration in old neurogenic niches. Nature (2019). https://doi.org/10.1038/s41586-019-1362-5

[5] Harris, L. et al. Coordinated changes in cellular behavior ensure the lifelong maintenance of the hippocampal stem cell population. Cell Stem Cell (2021). https://doi.org/10.1016/j.stem.2021.01.003

Smart mouse

Senolytic Navitoclax Rescues Neurogenesis and Memory in Mice

Scientists have shown that clearing senescent neural precursor cells with the senolytic drug navitoclax reverses the age-related decline in neurogenesis and improves spatial memory in mice [1].

Not to be replaced

The brain is an organ of special concern for geroscientists. It is theorized that we might soon be able to replace many aging organs, such as the kidneys, liver, or heart, but for obvious reasons, it is impossible to replace the brain. Since the brain is prone to age-related decline that leads to dementia, we must find a way to maintain it in working order for as long as possible.

Neurons are very long-lived cells that do not proliferate. All neurons differentiate from multipotent neural precursor cells (NPCs) that are, in turn, a product of differentiation of neural stem cells. Until the 1990s, it had been thought that neurogenesis – that is, the creation of new neurons – does not happen in an adult brain at all. Now we know of two or three regions in the brain, most notably the hippocampus, where adult neurogenesis continues, although its pace slows significantly as we age.

The reasons for this decline are not well known, but research shows that reduced neurogenesis in the hippocampus is firmly linked to the development of Alzheimer’s disease [2]. In this new paper, a group of scientists analyzed the role of cellular senescence in the age-related decline in hippocampal neurogenesis and how it can be mitigated by a popular senolytic Navitoclax.

Senescence slows neurogenesis

First, the researchers confirmed that neurogenesis slows in mice beginning at a young age. In their experiments, between 6 weeks and 3 months of age, the number of immature neurons in the hippocampus decreased by 50%, and by the end of the first year of life, the difference rose to a whopping 90%. That is, by the time mice reach middle age, their hippocampal neurogenesis almost grinds to a halt. Interestingly, the number of neural stem cells did not decline, but these stem cells were much less proliferative than in young age and produced fewer NPCs.

This decline in neurogenesis coincided with the accumulation of senescent cells in the hippocampus, as the researchers showed by analyzing several senescence markers, such as ß-galactosidase (ß-Gal). Most senescent cells happened to be NPCs.

Can an anti-cancer drug help?

Navitoclax is an experimental anti-cancer drug that induces apoptosis (cellular death) in senescent cells. It is one of the most well-researched senolytic compounds. Navitoclax proved to be effective in killing senescent NPCs, both in vitro and in vivo. In mice, navitoclax treatment eliminated 45% of ß-Gal-positive cells in the hippocampus, most of them NPCs. More importantly, the treatment led to an almost 50% increase in the number of immature neurons, indicating strong recovery of neurogenesis.

To confirm that neurogenesis rebounds due to the clearing of senescent cells, the scientists constructed a noteworthy genetic model of cellular senescence. They inserted an artificial gene into the promoter of another gene that produces the protein p16, which is a marker of cellular senescence. This transgene coded for a toxic protein and could be turned on by an introduction of a certain drug. That means that when the scientists introduced the drug into the mice’s hippocampi, it killed off only those cells that were expressing p16 – i.e., senescent cells. This genetic ablation of senescent cells recapitulated the neurogenesis-stimulating effect of navitoclax.

Hippocampus plays a crucial role in our memory function, especially in spatial memory [3]. Consequently, the reinvigoration of hippocampal neurogenesis led to a significant improvement in the spatial memory of 12-month-old mice.

The authors conclude that senescent cells “directly contribute to neurogenic decline in the middle-aged hippocampus, and that clearance of these cells can partially restore hippocampal neurogenesis and function”. Not only do senescent NPCs stop producing neurons themselves, the SASP also seems to adversely affect the differentiation of the neighboring non-senescent cells – not just of NPCs, but of their precursors, neural stem cells, as well.

Conclusion

Cellular senescence is clearly associated with aging, but this relationship is very complex, and scientists continue to elucidate its specific aspects. This new paper shows that eliminating senescent cells from the hippocampal niche can reverse the age-related decline in neurogenesis and can potentially be effective against dementias, such as Alzheimer’s disease. The fact that the drug used was a known anti-cancer medication underscores the systemic impact of cellular senescence.

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

Literature

[1] Fatt, M. P., Tran, L. M., Vetere, G., Storer, M. A., Simonetta, J. V., Miller, F. D., … & Kaplan, D. R. (2022). Restoration of hippocampal neural precursor function by ablation of senescent cells in the aging stem cell niche. Stem Cell Reports.

[2] Mu, Y., & Gage, F. H. (2011). Adult hippocampal neurogenesis and its role in Alzheimer’s disease. Molecular neurodegeneration, 6(1), 1-9.

[3] Broadbent, N. J., Squire, L. R., & Clark, R. E. (2004). Spatial memory, recognition memory, and the hippocampus. Proceedings of the National Academy of Sciences, 101(40), 14515-14520.

Rejuvenation Roundup January

Rejuvenation Roundup January 2022

Rejuvenation biotechnology is beginning to pick up steam, with major companies, political activism, and new approaches on the horizon. Let’s see what’s been done in January.

LEAF News

AL4I PanelCreating Political Action to Increase Healthy Human Lifespan: A recent online discussion panel revealed some valuable insights into the political aspects of increasing healthy human lifespans. Perhaps the most exciting part of the panel involves the idea that getting politicians to support longevity/aging therapeutics might not be as hard as people may think.

EARD2021

Drugs to Reverse Atherosclerosis [Repair Biotechnologies]: Reason, the CEO of Repair Biotechnologies, discussed a new method of enabling macrophages to consume cholesterol without turning into foam cells, dying, and leading to atherosclerosis.

Lifespan News

Altos Labs Announces Billions: Ryan O’Shea talks about how one of the market’s biggest players, well-known Amazon mogul Jeff Bezos, is putting forward money to fight against aging. Altos Labs is developing technology to bring cellular epigenetics back towards a youthful state.

LSN Altos Not LongevityIs Altos Labs a Longevity Company?: Despite working on epigenetic reprogramming, which is one of the hallmarks of aging, Altos Labs has expressly denied being a longevity company. Ryan O’Shea explains why that might be the case.

Is Aging a Disease?: World Health Organization included aging in the International Classification of Diseases, version 11. This doesn’t change the biology of aging, but it could change how it is perceived by the medical community.

Rejuvenation Roundup Podcast

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

Journal Club

CAR T Cells Produced in Vivo to Treat Cardiac Injury: Hosted by Dr. Oliver Medvedik, Journal Club has returned on Tuesday 25th January at 12:00 Eastern and was broadcast live on the lifespan.io Facebook page. This month’s paper was on how cells can be produced in living organisms in order to treat heart damage.

Interviews

Brian KennedyDr. Brian Kennedy: From Sickcare to Healthcare: Dr. Brian Kennedy is a longevity heavyweight: a former President of the Buck Institute, currently a Distinguished Professor in the Department of Biochemistry and Physiology at the National University of Singapore, a co-editor of Aging Cell, and one of the researchers behind a recent study of alpha-ketoglutarate that resulted in winding back chronological age in humans.

Sonia Arrison: “Aging Is One of the Last Unifying Issues”: Sonia Arrison is an entrepreneur, investor, and best-selling author. She discusses how aging is something important enough to bring together people on opposite sides of the political divide

Education

First pig-to-human heart transplant: what can scientists learn?: Transplanting genetically modified pig hearts into people has been a long-held dream, and this article from Nature explores the details of the procedure and how well it has worked.

ALEC is a lifespan comparison tool for researchers.The Animal Life Expectancy Comparisons Research Tool (ALEC): Dr. Leon Peshkin talks us through a new open access research tool that he has helped to develop and that is free for researchers to use now. The goal is to test whether animals subjected to an intervention show a statistically significant difference in lifespan compared to a control group.

Advocacy and Analysis

Debate Rages on the Inclusion of Old Age in the ICD-11: A significant debate has originated regarding the inclusion of MG2A, a code for old age, in the ICD-11 for Mortality and Morbidity Statistics. The 11th revision of the International Classification of Diseases, which goes into effect this month, is managed by the World Health Organization.

Objecting to Rejuvenation is Objecting to Medicine: Some people are uneasy about the idea of extending human healthy lifespan by using rejuvenation technologies that target the aging process directly, or they not always convinced that developing them is a good idea. This article looks at the question from a different perspective, asking what people from medieval Europe would think of current biotechnology.

Turning back the clockA Current Overview of Rejuvenation Techniques: Vadim Gladyshev and his team have published a review in Aging Cell about the current techniques and innovations in rejuvenation biotechnology, providing an overview of how these researchers see the state of the field.

Research Roundup

A Relationship Between Senescence and Respiratory Infections: A study published in Aging Cell has shown that senescent cells impact the way that CD4 T cells differentiate into types and that senolytics can restore this differentiation to a more youthful one.

Exercising GroupBenefits of Exercise Can Be Transferred via Plasmapheresis: Scientists have transferred the neuroprotective effects of exercise to sedentary mice via plasma transfusion and identified an obscure protein that might be responsible for the effect.

The Effects of Spermidine on Heart Mitochondria in Mice: The latest research published in the Journal of Anatomy found that spermidine alters the morphology of mitochondria in aged mouse heart tissue.

Spinach leavesA Supplement Combination Improves Memory in Older Adults: An open-access human study published in Clinical Nutrition has found that a combination of supplements is beneficial for working memory. The authors highlight some of the specific dietary components that selectively accumulate in the brain with biochemical effects.

Osteopontin Bone Remodeling May Be Key to Arthritis: A study published in Aging has found that osteopontin’s effects on bone remodeling may be at least partially responsible for osteoarthritis.

Synaptic TransmissionNew Combination Treatment Shows Promise Against Dementia: Scientists have combined the popular antibiotic rifampicin with resveratrol to create a possible preventative treatment for age-related dementias.

Genetically Engineered T Cells Reduce Cardiac Fibrosis: Scientists have created genetically engineered T cells that target activated cardiac fibroblasts in a transient manner, alleviating symptoms of cardiac injury.

KillifishIsthmin 1 as a Biomarker and Therapeutic Target for Aging: A recent study published in Biogerontology has discovered a potential new aging biomarker and longevity therapeutic target. Ism1 is not a well-known protein, but it has been shown to play a role in multiple aspects of biology.

The Effects of Metformin and Lifestyle on Mortality: An outcomes study conducted by the Diabetes Prevention Program (DPP) has examined the effects of lifestyle interventions and the popular diabetes drug metformin on all-cause mortality.

Parkinson'sKey Parkinson’s Protein Required for Immune Function: A study published in Cell Reports has found a-synuclein, the fundamental protein of Parkinson’s disease, to be critical in immune function.

A Nitrone Compound Protects the Spinal Cords of Mice: Publishing in GeroScience, a team of Oklahoma City researchers has found that a nitrone compound with a low molecular weight, OKN-007, maintains motor neuron functionality in the spinal cords of aging mice.

Small food amountFasting-Mimicking Diet Helps Fight Cancer: In the first human trial of its kind, scientists showed that a fasting-mimicking diet can work synergistically with conventional therapies in cancer patients, altering their metabolisms and reshaping their immune systems.

Quercetin Improves Bone Regeneration in Older Rats: A new study in ACS Applied Materials and Interfaces used a combined geroscience and tissue engineering approach to regenerate bone in aged rats. Tissue engineering and longevity therapeutics are often viewed as competing strategies, but this study proves how they can synergize.

Hearing LossEpigenetic Age Acceleration Is Linked to Hearing Loss: Using the long-running Baltimore Longitudinal Study of Aging as its data source, a study published in Frontiers in Aging Neuroscience examined the relationship between epigenetic age acceleration and hearing.

Heat Shock Protein Fights Senescence in Macular Degeneration: Researchers publishing in Experimental Eye Research have discovered that the peptide aB-crystallin can reduce the cellular senescence that affects the progression of age-related macular degeneration (AMD). aB-crystallin is a well-known heat shock protein, a family of proteins that is used in temperature regulation.

NeuronsTelomerase Alleviates Alzheimer’s Symptoms not via Telomeres: Scientists publishing in Nature Aging have shown that telomerase reverse transcriptase slows neurodegeneration in a way that doesn’t have anything to do with its telomere-building activity.

Cellular Reprogramming Rejuvenates Multiple Organs in Mice: In a preprint showcased in bioRxiv, scientists have shown that a single cycle of partial cellular reprogramming, which resets cells back to a youthful epigenetic state, can reverse multiple age-related changes in mice, including in the spleen and liver.

Balanced stonesMeta-Analysis Discovers Goldilocks Zone for IGF-1: A new meta-analysis from Aging Cell has shown that both high and low levels of IGF-1 are related to mortality risk. Insulin-like growth factor 1 (IGF-1) IGF-1 is one of the body’s major metabolic hormones. It can have effects similar to insulin, and it mediates the effects of growth hormone.

Dietary Fiber and Probiotics Affect Melanoma Immunotherapy: A study published by Dr. Jennifer A. Wargo and her colleagues spanning multiple centers recently examined if dietary fiber and commercially available probiotics affect immunotherapy response in cancer patients. They hypothesized that bacteria from two probiotic species would be associated with a response to this therapy.

Rat mazeSenolytics Restore Cognitive Ability in Aged Rats: Polish researchers publishing in Aging have discovered that the well-known senolytic combination of dasatinib and quercetin improves the cognitive capabilities of older rats through improving the plasticity of dendrites.

Affecting Basic Metabolism to Reduce Senescence: Publishing in Aging, a group of Korean researchers has discovered a compound that affects the way our mitochondria process energy, ameliorating cellular senescence.

Acute multidrug delivery via a wearable bioreactor facilitates long-term limb regeneration and functional recovery in adult Xenopus laevis: The first step was to stimulate limb regeneration in frogs; ideally, this research can continue to be successful in small mammals and people.

Mitochondrial transplantation improves anxiety- and depression-like behaviors in aged stress-exposed rats: Overall, mitotherapy improved anxiety-and depression-like behaviors in aged rats and it could be considered as a new therapeutic strategy for age-related depressive disorders.

Transfer of the longevity-associated variant of BPIFB4 gene rejuvenates immune system and vasculature by a reduction of CD38+ macrophages and NAD+ decline: In conclusion, the new senotherapeutic action of LAV-BPIFB4 may offer a valuable therapeutic tool to control aging and reduce the burden of its pathophysiological disorders, such as cardiovascular diseases.

Effect of Urolithin A Supplementation on Muscle Endurance and Mitochondrial Health in Older Adults A Randomized Clinical Trial: Although the improvements in the 6-minute walk distance and maximal ATP production in the hand muscle were not significant, long-term urolithin A supplementation was beneficial for muscle endurance and plasma biomarkers, suggesting that urolithin A may counteract age-associated muscle decline.

Association of Metformin with the Mortality and Incidence of Cardiovascular Events in Patients with Pre-existing Cardiovascular Diseases: Metformin use is associated with a reduction in all-cause mortality, cardiovascular mortality, incidence of coronary revascularisation, and heart failure in patients with cardiovascular disease; however, metformin usage was not associated with reduction in the incidence of myocardial infarction, angina, or stroke.

Oral Administration of Nicotinamide Mononucleotide Increases Nicotinamide Adenine Dinucleotide Level in an Animal Brain: These results demonstrate that oral gavage of 400 mg/kg NMN successfully increases brain NAD+ levels in mice after 45 min. These findings provide evidence that NMN may be used as an intervention to increase NAD+ levels in the brain.

Low-dose chloroquine treatment extends the lifespan of aged rats: Collectively, these results suggest that low-dose chloroquine alleviates senescence in prematurely aged stem cells.

DunedinPACE, a DNA methylation biomarker of the pace of aging: DunedinPACE showed high test-retest reliability, was associated with morbidity, disability, and mortality, and indicated faster aging in young adults with childhood adversity.

Differential Effects of One Meal per Day in the Evening on Metabolic Health and Physical Performance in Lean Individuals: A single meal per day in the evening lowers body weight and adapts metabolic flexibility during exercise via increased fat oxidation, whereas physical performance was not affected.

The Danaid Theory of Aging: The researchers argue that, in complex forms of life like humans, various restrictions on maintenance and repair may be inherent, and they show how such restrictions are laid out during development.

News Nuggets

Launch ButtonAltos Labs’ $3 Billion Launch to Reverse Cellular Aging: In September 2021, we reported that Altos Labs was about to launch an ambitious project to develop partial cellular reprogramming to the point where it could be safely used in humans to reverse cellular aging. That launch has now officially started, and Altos Labs is shaping up to be a real contender in the battle against epigenetic alterations.

A New Startup Is Going After Rogue Cells: In a blog post, the founder and CEO of Arda Therapeutics, Adam Freund, explained his company’s intriguing strategy along with why it is imperative to counter 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.
Colorful mitochondria

Targeting Metabolism To Slow Down Aging

Publishing in Aging, a group of Korean researchers has discovered a compound that affects the way our mitochondria process energy, ameliorating cellular senescence.

A deep dive into biochemistry

To begin their paper, the researchers discuss the role of the SASP, the inflammatory cytokine IL-33, and the relationship between mitochondria, ADP, and ATP. It is well known that the mitochondria are the powerhouses of the cell, but it is less known that they form an electrical potential across their membranes. A compound called ATP synthase 5, which itself is formed of protein subunits, uses this electrical potential in order to turn ADP and the electrical potential into ATP, which our cells use as energy [1].

Some of the subunits of ATP synthase 5 are referred to as alpha and beta. These two compounds form a heterodimer, a complex between two molecules. The catalytic site in the center of this heterodimer is where the conversion from ADP to ATP actually occurs [2].

Where IL-33 comes in

Seeking to confirm and understand a link between IL-33 and cellular senescence, the researchers tested 20 different compounds known to inhibit IL-33. They found that these compounds acted directly on a protein with the unusual name of 14–3–3?. Research was continued on the most promising of these compounds, which was defined as the one that promoted cellular proliferation the most: KB1541.

The researchers found that 14–3–3ζ, which is promoted by KB1541, regulates the function of ATP synthase 5, and computer modeling helped them to understand the exact physical way in which this occurs. They also used a specific point mutation of mice in order to confirm this; mice with slightly altered 14–3–3ζ received no benefit from KB1541.

A fundamental antioxidant

The effects of the regulation were demonstrated by how the resulting ATP synthase complex processes energy. The researchers found that KB1541 caused more ATP to be synthesized from oxygen phosphorylation and less from oxygen-less glycolysis. The amount of reactive oxygen species (ROS), a well-known contributor to cellular damage, was decreased in kind.

This reduction in ROS was then shown to lead to a decline in the characteristics of cellular senescence. KB1541 is not a senolytic; it does not kill senescent cells. Rather, it seems to function as a senomorphic, transforming cells from a senescent state into a more healthy one, as affected cells lost much of their mitochondrial mass, a characteristic of senescence.

Additionally, KB1541 was shown to increase autophagy, the method by which cells consume the damaged parts of themselves. SA-ß-gal, a well-known marker of cellular senescence, was found to be decreased.

Conclusion

Life extension research does not often dive this deeply into the specifics of biochemistry. Understanding the basic biology of every part of the human body would require a phenomenally complex computer system, and current technology only allows us to research one small part of biology at a time.

However, this research seems to have borne fruit. By directly affecting how our mitochondria process oxygen when forming energy from ATP, KB1541 appears to be a potentially viable method for tackling cellular senescence and possibly some aspects of mitochondrial dysfunction. Further research will need to be done to determine if this compound can ameliorate at least one of the root causes of aging, and age-related diseases, in human beings.

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

Literature

[1] Kühlbrandt, W. (2015). Structure and function of mitochondrial membrane protein complexes. BMC biology, 13(1), 1-11.

[2] Féthière, J., Venzke, D., Diepholz, M., Seybert, A., Geerlof, A., Gentzel, M., … & Bo¨ttcher, B. (2004). Building the stator of the yeast vacuolar-ATPase: specific interaction between subunits E and G. Journal of Biological Chemistry, 279(39), 40670-40676.

Sonia Arrison

Sonia Arrison: “Aging Is One of the Last Unifying Issues”

Sonia Arrison is an entrepreneur, investor, and best-selling author. Her book “100 Plus: How the Coming Age of Longevity Will Change Everything”, published in 2011, was one of the first to bring the topic of longevity to the general public’s attention. Sonia is also founder of 100 Plus Capital and Chair of the Alliance for Longevity Initiatives, a groundbreaking bi-partisan non-profit aimed at educating and influencing politicians and public opinion.

Your book on life extension was a pioneering one, written more than a decade ago. How would you describe this decade? Are you satisfied or disappointed with how things have been going in the longevity field?

First, it’s hard to believe a whole decade has gone by. Time flies fast, and the older you get, the faster it flies. I think, on the science and the business front, things are going well. None of us in the movement will be satisfied until we actually have full-on longevity-enhancing therapies on the market, but we’re going in the right direction. Science is going in the right direction. As Cynthia Kenyon once said to me, science always moves faster than you think it will, and it always moves slower than you think it will. So, you’re always surprised, and that’s just how it is, but it is moving and that’s good.

For instance, many things are different from 10 years ago. AI is much more ingrained in every aspect of research. There used to be separate AI companies and bio companies, but now almost every bio company uses AI.

What I’m disappointed in though, or definitely not satisfied with, is progress made on this issue in society. Public policy and regulations haven’t kept up with the science. I think it’s just a matter of educating the public and politicians as to what’s happening in the healthspan field. And here, we should note that it’s better to discuss our goal of extending healthspan rather than using the term longevity, because what everybody cares about is being healthy.

By the way, one of the things I liked about your book was how unabashed you were about lifespan extension, including extreme life extension. Interestingly, during this decade it became almost inappropriate to talk about, it’s more healthspan now.

I think the thing that most people care about is health, right? So, the term healthspan is very useful because that’s what most scientists are aiming at. They’re trying to extend health, but of course, if you can extend health long enough, then it turns into healthy longevity.

I don’t think it helps anybody to try to predict how long anyone’s going to live. It’s just not useful to say, well, maybe we could live to 500 or to 1000 years. That’s because just living to a healthy 150 years would be great at this point. Wouldn’t it be great if we could do that? And once we get over that hump, then we can start talking about 500 years, but now it’s too early to do that, it’s wildly aspirational.

There have been some bumps along the road, though, some setbacks, like with senolytics and resveratrol, both of which were mentioned in your book. What are your thoughts on that?

Well, there are always going to be failures. Every sector has big failures, that’s not uncommon. I don’t think we should be put off by that. And certainly, investors aren’t put off by that. I live in Silicon Valley, and, as you know, here we see companies fail all the time.

So now crypto is a huge thing, but way back when I first moved to California in 1999, payment companies were just starting to come into fruition. There was all this talk about replacing currency, and PayPal was just getting off the ground, and there were competitors that were trying to do the same thing as PayPal, and a bunch of them failed, and we don’t talk about them anymore. It’s the same thing in the bio space: there will be a bunch of companies that fail at something, and then there will be one big winner, and it’s going to be a huge win. And nobody’s going to remember any of the rest.

In the decade since the book was published, life expectancy in the US plateaued and even decreased for certain groups. Is this something that worries you?

It worries me from a societal perspective, because a lot of the reasons for the decrease in life expectancy are lifestyle- and society-based, like the opioid epidemic. It really is one of the big drivers of life expectancy going down, but it’s specific to some groups of people. That really is worrisome because we don’t want this going in the wrong direction. Nobody wants to see people dying sooner than they should based on life expectancy tables.

The goal is for people to be healthy, productive, and happy. So, when we see dips in the life expectancy of certain groups of people, it is worrisome, and it increases divides within society. In the ethics chapter of my book, I discuss this divide between the haves and the have nots. To me, one of the biggest problems that we could face in the future, is that there could be a big lag in the rollout of  life-extending technologies to some groups.

Historically, the wealthy have always had access to new technology before everyone else. Remember those big cell phones in brief cases? But, if the time lag between the wealthy and the poor getting access is too long, that could create real problems. This is why it’s very important that when the technology does hit the marketplace, there are ways to make sure it reaches all areas of society in a reasonable amount of time. When it comes to digital technologies, the marketplace often takes care of this issue, so hopefully new biotechnologies that make heavy use of the digital will fall in this category as well.

You are the Chair of the newborn Alliance for Longevity Initiatives. Please tell us about A4LI, why we need it, and how it differs from previous attempts to influence politicians on the issue of life extension.

We are the first 501(c)(4) to lobby for longevity. We’re very proud of that. Being a 501(c)(4) allows us to lobby politicians directly. It also allows us at some point to create a super PAC so we can raise money to support politicians in the electoral cycle. We plan to be very active in monitoring politicians and having a database of which ones are pro-longevity and which ones aren’t and trying to get more of them on the pro-longevity side. Right now, it’s sort of a blank slate because a lot of them don’t even know about this issue.

That’s why we’re so necessary. Somebody needs to go around DC and talk to all the politicians and explain to them why this is the biggest issue that they should be focusing on – particularly the representatives that are interested in healthcare, because this is the next level of healthcare, right? It’s about trying to keep Americans healthy rather than responding to the health crisis after it happens. We see that one of the problems with our system is that we don’t focus enough on prevention, we are very reactive. This has to change.

Not only are we going to lobby politicians, we’re also going to attempt to educate the public. That’s a part of our mission. We’ll be releasing primers and polls, reaching out to communities to make sure that people understand that this is something they can be talking to their politicians about. If you have a relative who’s sick with one of the diseases of aging, like cancer or Alzheimer’s, then aging is the root of your problem.

I like the bipartisan nature of A4LI, especially in these divisive times. Why does this cause bring politicians with different world views together, and how does ideology affect their views on life extension?

I think this is one of the last issues that people on both sides of the aisle can actually agree on. This makes it an exciting area to work in because it’s nice to be able to bring people together, especially since we see so much fighting on the national stage these days. So, it was great to have at our launch event Steve Israel from the Democrats and Newt Gingrich from the Republicans agreeing with each other. Steve Israel was like: “I’d never thought I’d be agreeing with Newt Gingrich, but here I am.” So, that’s nice. It’s very uplifting. After all, everybody wants to be healthy.

Do you also have disagreements?  After all, people from the two sides of the aisle might view the question of longevity differently. In your experience, what works best for whom – for instance, economic or humanitarian arguments?

These are not disagreements but different reasons for why people are there. Ideology does have an impact on why people are supporting the longevity movement. Interestingly, the economic and humanitarian arguments kind of go together. You would think (and maybe to some extent, this is true) that the conservatives are more swayed by the economic argument and the liberals are more swayed by the humanitarian argument, but honestly, I think everybody is swayed by the humanitarian argument.

If you go back and watch our launch event, Newt Gingrich said that while the economics matter, the humanitarian part is even more important: you don’t want to see your loved one suffering from Alzheimer’s. So, everybody from every political perspective seems to agree on that.

Yes, this might be the biggest common denominator ever.

Yes, it really is. But after you get past that common denominator, you see that the conservatives are much more interested in the economics and the national security benefits of longevity, and in the economic competitive advantage that having a healthier workforce gives.

To the extent that we can beat China, or whoever our adversary is at the time, through having a healthier workforce, the conservatives will be all for that. And on the more liberal side, or the Democratic side, I think people are more interested, say, in universal health. They are much more convinced by the equalization argument: we need universal health, so that everybody can have an equal footing to live their best life. But everybody can still agree on the necessity of prolonging healthspan.

But are the conservatives ready to pour a lot of budget money into it?

I think they will be once they understand what it’s about. We are at this nascent stage right now where not many politicians understand why this is going to be so epic and paradigm-shifting. And once they understand that, I could imagine our military leaders saying, yes, we need to push this longevity agenda now because it’s a national security issue.

And I would argue that there’s even an economic argument for the left: look, if we don’t have to spend so much money on healthcare, Medicare, all those services, we can pump that money back into things like education and universal kindergarten – we can repurpose all that wasted money that’s currently spent on procedures and pills that don’t actually cure anyone.

Or maybe, with healthcare costing less, it will be easier to push the case for universal healthcare.

Perhaps. The less expensive it is, the easier it would be for the government to take it on.

Did the onslaught of COVID, a clearly age-related disease, change attitudes toward life extension? Do you see an increased sense of urgency?

One of the silver linings of COVID is I that it has made people much more aware of the fact that aging is a risk factor. I mean, everyone kind of knew it already – that you don’t tend to get cancer or heart disease until you get old, but we just saw that as something natural and it didn’t hit us that hard. But with COVID it was clear, obvious, and in your face – that aging is a serious risk factor for disease. That’s really woken a lot of people up.

Funny enough, I think it may have resonated more with the younger people than with the older people. This is just anecdotal, of course. I don’t have any data on this, but I feel like young people are even more energized about that anti-aging agenda now because they see the carnage and they’re like, wow, we need to stop this from happening again.

Yes, I see a lot of young people in our field. I think, when we first learn about death at a young age, it really hits us hard, and later we get used to it. But now people can actually act on this.

Right, before it gets to them. They’re like, wait, if there are other things like COVID, maybe we should try to stop them before we get there.

Your background is technology analytics. What are the most important contributions by technology to geroscience today?

Well, AI is probably the most important thing that happened. There are other things, like 3D modeling, 3D printing, the ability to build up big computing platforms, big data, et cetera. But I think there’s also a sort of a more ideological thing that came from technology in that a lot of people now see biology as an engineering project, rather than just a kind of a black box thing that we can’t and shouldn’t try to touch. I think, now there are more people who are saying, well, let’s just open that box and see what’s in there and if we can re-engineer some stuff.

But in a way, AI also makes biology a black box, because we put in the data, we receive the results, we can verify them, but we might not have the slightest idea how it works.

Yes, that is true, except that with the biology, researchers also don’t create the thing that’s going in and the thing that’s coming out. With AI, at least you code the thing that’s going in, so there’s a little bit more control over the process, but you’re right, AI is also kind of nebulous.

Anyway, the point is that there’s a lot more human capital coming into the field now because it’s seen as an engineering project, and that’s one of the major contributions from the tech industry.

Which directions and discoveries in the longevity field make you especially optimistic? How do you see the timeline for anti-aging interventions?

There are a lot of exciting areas of research in aging – senolytics, regenerative medicine, and gene therapy, to name a few. But I really try to not have a timeline. I think it’s dangerous and not helpful to try to make predictions, because you never know when the next huge breakthrough is going to happen. So, I really hesitate to ever try to make any kind of predictions about when any of this is going to happen.

I will say that there are more shots on goal today than there ever were, and that means it’s more likely that we’ll actually get one in the net. This makes me optimistic not about any particular type of science, but just because of the fact that there are more directions now and more people working on them. It’s inevitable that at some point, a really big breakthrough is going to happen.

What are the guiding principles behind your investments in biotechnology?

I don’t invest in science projects. A lot of people come to me with a science project that you can’t turn into a business just yet. Maybe it will be a business, but it might take another five or 10 years. So, one of my principles is that it has to be translatable. You have to be able to turn it into a product of some sort that you can make money from selling. That’s a really basic principle for me.

Then, I look for things that shift the paradigm, that really push the envelope and are going to make a huge contribution, because I only make a limited number of investments. So, I’m trying to invest in things that are going to be really epic, which means many of them are very risky, they’re not sure things, not just another iteration of something else.

The team has to be right. This is really important, because sometimes, I see companies that have a great idea, they’ve got great technology, and it is a business, but the team is just… you know they’re not going to be able to execute. It’s painful because you just want to tell them, but even if you tell them the reason that you’re not investing, they don’t go and change their team. They just try to find a different investor.

Do you have specific criteria for this, or do you just meet the team, and you immediately see they’re not up to the task?

It’s just meeting the team and seeing whether or not the team members agree with each other. Sometimes they’ll start arguing in a pitch meeting, and that’s a very bad sign. Another question is, how on top of things are they? Do they have all the data together? Are they organized? Do they look like a team that’s going to be able to execute, or are they sort of a disheveled professor who has this great idea, but they never going to be able to take this somewhere because they don’t have a plan? There has to be a plan.

Do you think there’s a lot of snake oil peddling going on in the field?

I think there’s still snake oil out there, which is unfortunate. I think this is the uniquely bad thing about our field in that the term originated in this area. But that said, there are scammers in every area of life, though some are easier to spot than others. I know a lot of VCs here in Silicon Valley who invest in software and it’s easier and faster to validate whether or not the claims of a particular software program are snake oil-like.

The last chapter of your book is dedicated to the leaders of the longevity field. Some names are still here, obviously, but what new names would you put on that list today?

Well, definitely Yuri Milner, with his Breakthrough Foundation and Altos Labs. Jim Mellon. Now, I don’t know if everybody would agree with me on this, but the division between longevity and healthcare is blurring, they’re sort of coming together, and this is great. Take the Chan-Zuckerberg Initiative. Just recently, a researcher who I know at Stanford who is doing amazing work on anti-aging solutions for the brain, got some big funding from the Chan-Zuckerberg Initiative. So, they are dedicated to healthcare as a whole, and they are also beginning to fund longevity research.

Also, this is not a single person, but the crypto community stepped up and they didn’t exist in this space before. I am so happy to see them. They really understand the engineering bit of it, and they’re very dedicated to learning, and they’re self-starting people. So, they are becoming really involved and they’re donating – they’re putting their money where their interests lie.

In your book, you quite expertly dismiss many arguments against life extension, but is there something about the ethical and societal aspects of it that you feel like you don’t have a fully satisfying answer to? For instance, I am not sure we have a convincing solution to the potential problem of vertical mobility, of old people making it hard for the younger generation to advance.

I don’t think this is going to be a problem. Yes, the older people will have broader networks, but those will be older networks of old people and the new people coming up as they do today, they make their own networks within their younger group. That younger group goes out and does things, and then the older people will be worse off because they weren’t part of it. Being the wiser, older people they are, they will know that they should not try to lock the young people out, because they will miss out on opportunities.

The great thing about longevity is that people tend to get wiser, if not smarter. They get to understand the value of working together. I think that when we’re young, we’re trying to just scrape our way up and don’t really value community. Once you’re older, you start to see the value of community and you can sit back and say, you know what? I don’t always have to be the winner or the leader. I can be part of the community, and everybody still wins.

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.
ARDA Therapeutics

A New Startup Is Going After Rogue Cells

In a blog post, the founder and CEO of Arda Therapeutics, Adam Freund, explained his company’s intriguing strategy along with why it is imperative to counter aging.

From Calico to Arda

It’s not every day that the longevity field sees a new player with a fresh message joining the ranks. On January 25th, Dr. Freund announced the arrival of Arda Therapeutics in a blog post. After completing his Ph.D. in molecular and cell biology at Berkeley, Dr. Freund was briefly a postdoctoral fellow at the Buck Institute under Judith Campisi, and then at Stanford, working on projects that focused on aging and cancer biology. Importantly, before founding Arda, Dr. Freund spent almost seven years as a principal investigator at Calico. Freund spoke about his work at Calico at last year’s Longevity Therapeutics conference.

According to Freund, Arda Therapeutics is backed by some well-known venture capital funds, including Andreessen Horowitz and The Longevity Fund. The company is also actively hiring, so we do not yet know who will join Freund on the scientific team.

More than senolytics

Arda proposes an interesting strategy based on eliminating harmful cells. This is already being done for cancer and senescent cells, but Freund makes an argument for a much wider approach based on the fact that many diseases are caused by dysregulation of a relatively small subset/subtype of cells. As an example, he mentions overgrowth of stromal cells that can lead to fibrosis and overactivation of certain immune cell types that causes chronic inflammation [1].

The traditional approach is to bring those cells back to normal with drugs, but this can be very challenging because of the immense complexity and interconnectedness of cellular processes, many of which are still unknown to us.

Rather that trying to fix misbehaving cells, it might be easier to simply eliminate them. Scientists know a great deal about the mechanisms of cellular death and how to trigger them. At times, the body can repopulate the niche, replacing the dead cells with healthy ones.

For this approach to succeed, such cells must be precisely identified. This is not an easy task, but recent advances in bioscience and AI can provide a roadmap. In this regard, Freund mentions single-cell sequencing that allows researchers to build much more detailed cell maps based on subtle differences between cellular subtypes. Interestingly, from the few papers that have been published by Calico, we know that its scientists use large-scale single-cell sequencing [2].

In cancer, trying to eliminate harmful cells involves harsh treatments that exert a heavy toll on the patient’s health and quality of life. According to Freund, the problem is that cancer cells proliferate uncontrollably, which is not the case with other harmful cells. As a result, to eradicate cancer, every single cancer cell must be killed, while to alleviate other diseases, it might be enough to simply lower the burden of “bad cells”. We would add that due to their fast proliferation, cancer cells continuously evolve to evade threats, which makes them an even more formidable adversary.

In his blog post, Freund is being remarkably honest about the challenges that lie ahead. For instance, even when a harmful subtype of cells is identified, it might be tricky to devise a precise targeting and delivery method. Yet, recent breakthroughs in this field, such as lipid nanoparticles [3], inspire hope.

Unabashedly anti-aging

Freund does not shy away from admitting that his company will target age-related diseases and aging itself, as he explains his beef with aging in a passionate and eloquent way:

For as long as I have been a scientist, I have been driven to understand aging. Frankly, I have trouble understanding why it’s not a more common obsession. After all, it’s going to kill you… At Arda, we hypothesize that there are shared biological mechanisms that affect multiple aspects of age-related deterioration, and that targeting those mechanisms is a promising path to extending healthy lifespan. More specifically, we suspect that many aspects of aging are driven by the hyper-activation of particular cell types, and that if we can remove those cells, we will delay (and possibly reverse) tissue deterioration. If we are even marginally successful, we will push back the greatest killer that has ever existed, improve quality of life at older ages, and give everyone more time with the people they love. We strive to not just add years to life, but life to years.

We at lifespan.io couldn’t agree more. Unfortunately, Freund’s attitude is in sharp contrast with some other companies, such as Altos Labs, that are trying to position themselves as strictly non-longevity, even though cellular reprogramming, the main avenue that Altos Labs will be pursuing, is more longevity-oriented than clearing out rogue cells.

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

Literature

[1] Thameem Dheen, S., Kaur, C., & Ling, E. A. (2007). Microglial activation and its implications in the brain diseases. Current medicinal chemistry, 14(11), 1189-1197.

[2] Roux, A., Zhang, C., Paw, J., Zavala-Solorio, J., Vijay, T., Kolumam, G., … & Kimmel, J. C. (2021). Partial reprogramming restores youthful gene expression through transient suppression of cell identity. bioRxiv.

[3] Li, Y., Su, Z., Zhao, W., Zhang, X., Momin, N., Zhang, C., … & Weiss, R. (2020). Multifunctional oncolytic nanoparticles deliver self-replicating IL-12 RNA to eliminate established tumors and prime systemic immunity. Nature Cancer, 1(9), 882-893.

Rat maze

Senolytics Restore Cognitive Ability in Aged Rats

Polish researchers publishing in Aging have discovered that the well-known senolytic combination of dasatinib and quercetin improves the cognitive capabilities of older rats.

Understanding neuroplasticity

While new neurons can be formed in the adult hippocampus through neurogenesis [1], learning and behavioral changes caused by changes in the prefrontal cortex are not the result of this process. Instead, neurons in the prefrontal cortex form protrusions called dendritic spines, which then go on to become synapses between other neurons.

Rather than the mass neuronal death seen in Alzheimer’s disease, it is this fundamental ability to form new connections that declines with “normal” aging [2]. The downstream effects of this gradual loss of ability affect practically every aspect of cognitive function, including reasoning, memory, psychomotor abilities, and your ability to remember and understand the contents of this paragraph along with my ability to write it.

As neuroplasticity is directly related to changes in gene expression, it has been shown to be strongly affected by epigenetics, specifically the methylation of histone H3 [3]. The researchers hypothesized that this change in gene expression is linked to the accumulation of senescent cells, specifically due to the senescence-associated secretory phenotype (SASP).

In order to test their hypothesis, the researchers administered the well-known senolytic combination of dasatinib and quercetin (D+Q) to rats.

A series of positive effects

In this experiment, rats were trained to avoid a specific place through small electric shocks. As expected, older rats performed worse on this task than younger rats, which learned to avoid the specific place quickly. However, rats that had performed poorly on this task performed very similarly to younger rats after an administration of D+Q, showing that their short-term memory and skill learning abilities were significantly improved, and they retained this improvement even five weeks after administration of D+Q had ceased. D+Q administration had no apparent effect on younger rats.

The researchers then examined the effects of the SASP on inflammatory cytokine levels. While each individual cytokine was not strongly affected, rats given D+Q had a broad decrease in nearly all of the cytokines tested, including interleukins and interferon-γ. The anti-inflammatory cytokine IL-10, which actually increases with aging, was further increased with D+Q in both young and old animals.

In the next step in this experiment, the researchers carefully examined the dendritic spines of the animals, focusing on the hippocampus. The basal dendrites were unaffected; however, the apical dendritic spines of aged animals given D+Q were shown to be thicker and substantially longer than those of their untreated counterparts, corresponding to their increased ability to retain memory and knowledge.

Finally, the researchers took a look at H3 histone methylation, where the differences were stark and clear. Correlating with cognitive decline, the methlylation of the H3K9me3 site increases with aging, while that of H3K27me3 decreases; D+Q treatment halved H3K9me3 while significantly increasing H3K27me3.

Conclusion

The role of inflammaging and the SASP on cognitive decline has remained an open question, and this study has significantly helped to close it. While senolytics have not been shown to affect diseases such as Alzheimer’s and are unlikely to be the last word in “normal” cognitive decline, this study shows that they have a significant effect on the ability of older animals to perform basic cognitive tasks, right down to the neuronal level.

As always, human trials are required to see whether or not these or any other senolytics have positive effects on the human brain and whether or not targeting inflammaging is a viable method of allowing older people to retain their cognitive abilities.

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

Literature

[1] Fares, J., Bou Diab, Z., Nabha, S., & Fares, Y. (2019). Neurogenesis in the adult hippocampus: history, regulation, and prospective roles. International Journal of Neuroscience, 129(6), 598-611.

[2] Bloss, E. B., Janssen, W. G., Ohm, D. T., Yuk, F. J., Wadsworth, S., Saardi, K. M., … & Morrison, J. H. (2011). Evidence for reduced experience-dependent dendritic spine plasticity in the aging prefrontal cortex. Journal of Neuroscience, 31(21), 7831-7839.

[3] Parkel, S., Lopez-Atalaya, J. P., & Barco, A. (2013). Histone H3 lysine methylation in cognition and intellectual disability disorders. Learning & Memory, 20(10), 570-579.

Fibrous foods

Dietary Fiber and Probiotics Affect Melanoma Immunotherapy

A study published in Science by Dr. Jennifer A. Wargo and her colleagues spanning multiple centers recently examined if dietary fiber and commercially available probiotics affect immunotherapy response in cancer patients [1]. They hypothesized that bacteria from two probiotic species would be associated with a response to this therapy.

The human patients

By using stool samples, the researchers examined the gut microbiomes of 438 patients with melanoma. Most of the patients were receiving systemic therapy for metastatic melanoma (n=321) and were classified as responders or non-responders based on Response Evaluation Criteria in Solid Tumors (RECIST).

Of these patients, 87% were receiving immune checkpoint blockade (ICB) immunotherapy. This type of therapy uses monoclonal antibody-based therapies to block the desired interaction at immune checkpoints. For instance, a common treatment used to prevent T lymphocytes from attacking other cells is an immune therapy called anti-programmed cell death 1 (anti-PD-1). Most of the patients in this study on ICB immunotherapy were also on anti-PD-1 immunotherapy. Data was collected on dietary habits and probiotic supplements used within the past month.

No significant differences with probiotic use in late-stage melanoma patients

49 out of 158 of the late-stage melanoma patients were on a probiotic supplement in the past month. The authors noted that the patients on the probiotics had lower BMIs, reported higher consumption of vegetables and legumes, and were less likely to be on statins than patients who were not taking a probiotic supplement. When looking at survival rates in patients treated with ICB immunotherapy, there were no significant differences between patients who took a probiotic supplement and patients who did not.

The effects of probiotics on larger tumors in mice

Germ-free mice received donor stool from responders as determined by RECIST. These mice were then given one of two types of commonly purchased probiotic strains, Bifidobacterium longum and Lactobacillus rhamnosus, as well as treatment with immunotherapy to treat the tumors. Compared to the control group, the mice on either of the probiotics had significantly larger tumors. The research found similar results when they did the same experiment in non-germ-free mice and specific pathogen-free mice that had melanoma tumors.

Probiotics vs. sterile water in mice

The researchers then examined mice fed either of two probiotic strains alongside a control group fed sterile water. The treated mice had reduced levels of two immune cell types that play important roles in helping to fight cancer: interferon-γ and CD8+ T cells. The treated groups also had reduced cytotoxic t-cells in tumor tissues, which are immune cells that aid in helping fight tumor cells. The authors cite research that has shown similar and opposite findings, and follow with:

Together, these studies support the need for more careful investigations of the effects of current commercially available probiotic formulations on immunity and cancer immunotherapy response.

Fiber slowed tumor growth in mice and humans

Among mice receiving an anti-PD-1 therapy, mice on a fiber-rich diet showed delayed tumor growth compared with mice on a fiber-poor diet. The researchers also profiled the gut microbiomes of the mice, and there were significant differences in the fiber-rich and fiber-poor diets. Immune cell analysis revealed that the mice fed a high-fiber diet had higher CD45+ T cells in their tumors and higher T cell activation and interferon responses.

To assess the effects of dietary fiber intake on ICB immunotherapy response in humans, the researchers chose the National Cancer Institute Dietary Screener Questionnaire. Even though a fiber intake of 20 grams per day was considered sufficient, only 30% of people on ICB immunotherapy, 37 out of 128, reached this level.

Additional analysis showed that higher fiber intake was highly correlated with vegetables, fruit, whole grains, and, to a lesser extent, calcium intake. People who ingested less than 20 grams per day were more likely to be classified as obese and to be on blood pressure-reducing medication.

Patients who consumed sufficient fiber demonstrated improved survival rates. After adjustment for clinical parameters, every 5-gram increase in fiber intake corresponded with a 30% lower risk of cancer progression or death. In this study, similar results were found when assessing dietary fiber intake in relation to ICB immunotherapy response. People who consumed sufficient fiber and did not take probiotic supplements had significantly greater survival rates. The authors follow the human diet data results with:

Ongoing dietary intervention studies in the setting of ICB are critical for establishing whether a targeted and achievable diet change at the initiation of ICB can safely and effectively improve outcomes (NCT04645680).

Conclusion

While the researchers stressed the need for further research and independent validation, this study shows that dietary fiber and probiotic use are associated with different outcomes in humans and mice on ICB immunotherapy.

This study highlights an overarching point and a valuable message for clinicians and patients: this type of research comes with a need for additional careful investigations with interdisciplinary and multi-center collaboration. Specific supplements may need to be taken with caution within the context of specific scenarios, such as ICB immunotherapy.

The authors concluded with:

These notable (and perhaps unexpected) findings from studies in this observational patient cohort are corroborated by parallel studies in preclinical models with preliminary mechanistic insights. In light of these collective results, dietary habits and probiotic supplement use should be considered in patients receiving ICB and in efforts to modulate the gut microbiota. These factors should be more thoughtfully evaluated in strategies to improve cancer outcomes.

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

Literature

[1] Spencer, C. N., McQuade, J. L., Gopalakrishnan, V., McCulloch, J. A., Vetizou, M., Cogdill, A. P., Khan, M., Zhang, X., White, M. G., Peterson, C. B., Wong, M. C., Morad, G., Rodgers, T., Badger, J. H., Helmink, B. A., Andrews, M. C., Rodrigues, R. R., Morgun, A., Kim, Y. S., Roszik, J., … Wargo, J. A. (2021). Dietary fiber and probiotics influence the gut microbiome and melanoma immunotherapy response. Science (New York, N.Y.), 374(6575), 1632–1640. https://doi.org/10.1126/science.aaz7015

Balanced stones

Meta-Analysis Discovers Goldilocks Zone for IGF-1

A new meta-analysis from Aging Cell has shown that both high and low levels of IGF-1 are related to mortality risk [1].

Insulin-like growth factor 1 (IGF-1)

IGF-1 is one of the body’s major metabolic hormones. It can have effects similar to insulin, and it mediates the effects of growth hormone. IGF-1 has growth-promoting effects in almost every tissue, inhibiting apoptosis and increasing the synthesis of proteins and DNA [2]. High expression of IGF-1 has been shown to reduce lifespan and healthspan in worms, mice, and flies [3-5]. In fact, the expression of very low levels of IGF-1 has increased mouse lifespan by as much as 40% [6].

Serum levels of IGF-1 are commonly measured in the clinic. This has provided researchers with a wealth of data on the hormone, but studies of IGF-1 levels in humans have shown mixed results. High IGF-1 is associated with an increased risk of several cancers [7]. However, low levels of IGF-1 are associated with diseases such as cardiovascular disease, diabetes, and frailty [8]. Many studies have linked both high and low levels of IGF-1 to mortality, while others have found no relationship [9].

Because of these conflicting results, it is unclear whether there is any value in measuring IGF-1 to predict remaining lifespan. However, an international collaboration of researchers recently conducted a meta-analysis of these findings to determine if an ideal range exists for IGF-1 to predict all-cause mortality [1].

IGF-1 shows a U-shaped relationship with mortality

19 studies that included a total of 30,876 participants were included in the meta-analysis. The studies were conducted from 2007 to 2018 and included populations from the United States, Japan, China, and various European nations.

First, the authors looked at high versus low IGF-1 and mortality, similar to the methodology of previous studies. In this analysis, no difference in risk of death was found between the high and low levels of IGF-1 groups.

Rather than only grouping participants into “high” and “low” levels of IGF-1, 9 of the studies included detailed enough information to conduct a dose-response meta-analysis. This analysis showed a U-shaped response, with both the lowest levels and highest levels of IGF-1 being associated with higher mortality.

The researchers then analyzed their dataset using an intermediate group that approximately aligned with the lowest mortality from the dose-response analysis (120-160 ng/mL). With low, intermediate, and high IGF-1 groupings, mortality risk still did not differ between high and low IGF-1 levels. However, the intermediate group had statistically significant lower mortality risks than both the high and the low groups. These findings did not change when the intermediate range was expanded to 100-180 ng/mL IGF-1 or when excluding studies that did not include participants older than 70.

Lastly, researchers used the Third National Health and Nutrition Examination Survey (NHANES III, 1988–1994) to see which dietary differences were correlated with IGF-1. Higher consumption of proteins, carbohydrates, and 13 different vitamins and minerals were associated with higher IGF-1 levels, as were eggs, milk, cheese, yogurt, and butter. These findings were similar to previous studies and confirm that IGF-1 levels can be modified by dietary changes.

In conclusion, by analyzing and comparing different ranges of IGF-1 in 30,876 subjects, we find that both high and low levels of IGF-1 increase mortality risk, and for the first time, we identify a specific mid-range being associated with the lowest mortality (120–160 ng/ml). Using the NHANES III survey, we show an association between high intake of animal proteins, carbohydrates, and milk-based products and IGF-1 levels. These results can point to diagnostic, nutritional, and pharmacological strategies to optimize IGF-1 levels and help reduce mortality.

Conclusion

IGF-1 has been of great interest to longevity researchers due to its key role in metabolism, influence on healthspan and lifespan in model organisms, and association with mortality in humans. Its association with mortality has been scrutinized in recent years with the publication of several seemingly conflicting results. This study appears to explain these contradictory findings by identifying the relationship between IGF-1 and mortality as U-shaped rather than linear.

As always, the conclusions that can be drawn from these sorts of studies are limited. It cannot be said whether low and high IGF-1 contributed to mortality in these participants or if it was simply correlated. Additionally, it is well established in the scientific literature that studies with nonsignificant results disproportionately go unpublished. While the authors did not detect any publication bias in their statistical analysis, meta-analyses can only be as good as the studies that go into them.

Ultimately, these results do well to highlight the complexity of aging biology. It is not always enough to simply lower the concentration of a protein that is problematic at high levels or raise one that is problematic at low levels. If the concentration is raised or lowered too far, it can become problematic once again. If the level of IGF-1 is a contributor to aging (as opposed to simply the result of aging), this study highlights for the first time an ideal “healthy” range and includes several dietary measures that may be used to modulate its concentration in the body.

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

Literature

[1] Rahmani, J. et al. Association between IGF-1 levels ranges and all-cause mortality: A meta-analysis. Aging Cell (2022). https://doi.org/10.1111/acel.13540

[2] Clemmons, D.R. Metabolic actions of insulin-like growth factor-I in normal physiology and diabetes. Endocrinology and Metabolism Clinics of North America (2012). https://doi.org/10.1016%2Fj.ecl.2012.04.017

[3] Fontana, L., Partridge, L., & Longo, V.D. Extending healthy lifespan—From yeast to humans. Science (2010). https://doi.org/10.1126/scien ce.1172539

[4] Kenyon, C. A pathway that links reproductive status to lifespan in Caenorhabditis elegans. Annals of the New York Academy of Sciences (2010). https://doi.org/10.1111/j.1749-6632.2010.05640.x

[5] Podshivalova, K., Kerr, R. A., & Kenyon, C. How a mutation that slows aging can also disproportionately extend end-of-life decrepitude. Cell Reports (2017). https://doi.org/10.1016/j.celrep.2017.03.062

[6] Bartke, A., Sun, L.Y., & Longo, V. Somatotropic signaling: Trade-offs between growth, reproductive development, and longevity. Physiological Reviews (2013). https://doi.org/10.1152/physr ev.00006.2012

[7] Renehan, A.G. et al. Insulin-like growth factor (IGF)-I, IGF binding protein-3, and cancer risk: Systematic review and meta-regression analysis. The Lancet (2004). https://doi.org/10.1016/s0140-6736(04)16044-3

[8] Higashi, Y. et al. IGF-1, oxidative stress and atheroprotection. Trends in Endocrinology & Metabolism (2010). https://doi.org/10.1016/j.tem.2009.12.005

[9] Burgers, A.M.G. et al. Meta-analysis and dose-response metaregression: Circulating insulin-like growth factor I (IGF-I) and mortality. The Journal of Clinical Endocrinology & Metabolism (2011). https://doi.org/10.1210/jc.2011-1377