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Building a Future Free of Age-Related Disease

Vaccination

A Potential Vaccine for Senescent Cells

The journal Nature has published a letter communication regarding a senolytic vaccination study [1]. These letters are typically research studies that the editor chooses to urgently publish due to the importance they hold for the other researchers in the field. They may or may not be peer reviewed before this publication.

Background

Senescent cells accumulate with age, and research also shows that they increase in response to metabolic stress [2,3]. Research has advanced substantially in senolytics, including a potential vaccine for senescent cells; however, concerns remain regarding their specificity and safety. Due to the heterogeneity of senescent cells, more research is underway on specific vaccines that can target senescent cells or tissues to eliminate unwanted senescent cells.

In this study, the authors sought to see if a specific glycoprotein vaccine could impact senescence, specifically one based on glycoprotein nonmetastatic melanoma protein B (GPNMB). GPNMB is a transmembrane protein, and it is also called osteoactivin [4], as it plays a role in bone formation [5]. GPNMB has other roles as well, but authors noted its role in the immune system as well as human aging [6]. The initial experiments they carried out in this study confirmed that GPNMB is upregulated in multiple tissues of mice and humans undergoing senescence.

Human cellular results

The researchers examined transcriptomic data and analyzed the expression profiles for two specific genes using the Gene Expression Omnibus Database. The results from a Western blot showed that when the young and middle-aged human umbilical vein endothelial cells (HUVEC) were compared to the older cells, the older replicative senescent cells had the highest gene expression of GPNMB as well as antibodies for p53 and p21, which serve as senescence markers. It was these results that made the researchers proceed forward with GPNMB.

Murine results

When GPNMB-positive cells were eliminated by the vaccine in mice fed a high-fat diet, it improved heart disease and metabolic dysfunction. Additionally, when examining the adipose tissues of these mice after the GPNMB-positive cells were removed, cellular senescence was decreased and metabolic abnormalities were improved.

To investigate normal aging, they carried out experiments on a mouse model of Hutchinson-Gildford progeria syndrome. They gave 50- and 70-week-old mice the GPNMB vaccine. When the vaccine was given, it caused a reduction in GPNMB cells, thus improving normal and diseased phenotypes associated with aging. Male mice lived approximately 3 weeks longer than females.

The researchers used a strain of mice engineered to express luciferase, a harmless light-emitting compound, in such a way that they would emit light when expressing the GPNMB gene. Some of these engineered mice were also deficient in apolipoprotein E, and apolipoprotein E knockout mice develop plaque in the aorta and are used to study heart disease [7]. When these mice were given the vaccine along with a high-fat diet, their heart disease burden was shown to be decreased compared to their unvaccinated counterparts.

An additional experiment was carried out in luciferase reporter mice treated with the GPNMB vaccine, a combination of the senolytics dasatinib and quercetin, or the senolytic drug navitoclax. Luciferase allowed the researchers to see how much of the GPNMB gene was expressed as a result of these interventions.

While all three groups had decreased luciferase expression in the abdomen, the vaccinated mice had more anti-GPNMB antibodies, improved blood glucose from 16 to 24 weeks, and improvements in the senescence markers SA-beta-gal and Cdkn2a through week 24. The D+Q and navitoclax groups only showed improvements through week 16, and despite improved blood glucose, both of these groups developed insulin resistance at 24 weeks of age. Additionally, the navitoclax group suffered from reduced white blood cell and platelet counts along with extended bleeding time.

Ultimately, this study showed many favorable transcriptomic changes from the GPNMB vaccine, which eradicates a specific set of senescent cells.

Conclusion

Collectively, these results show that a vaccine that targets GPNMB could be a potential method for the development of new precision senolytics. The authors were unable to rule out whether it was the elimination of senescent cells expressing low levels of GPNMB or non-senescent cells expressing high levels of GPNMB that contributed to the beneficial effects of the vaccine. Further investigation is needed to learn how GPNMB vaccination could affect the immune system and its potential role in lifespan and healthspan.

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] Suda, M., Shimizu, I., Katsuumi, G. et al. Senolytic vaccination improves normal and pathological age-related phenotypes and increases lifespan in progeroid mice. Nat Aging (2021). https://doi.org/10.1038/s43587-021-00151-2

[2] Campisi J. (2005). Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors. Cell, 120(4), 513–522. https://doi.org/10.1016/j.cell.2005.02.003

[3] Childs, B. G., Gluscevic, M., Baker, D. J., Laberge, R. M., Marquess, D., Dananberg, J., & van Deursen, J. M. (2017). Senescent cells: an emerging target for diseases of ageing. Nature reviews. Drug discovery, 16(10), 718–735. https://doi.org/10.1038/nrd.2017.116

[4] Shikano, S., Bonkobara, M., Zukas, P. K., & Ariizumi, K. (2001). Molecular cloning of a dendritic cell-associated transmembrane protein, DC-HIL, that promotes RGD-dependent adhesion of endothelial cells through recognition of heparan sulfate proteoglycans. The Journal of biological chemistry, 276(11), 8125–8134. https://doi.org/10.1074/jbc.M008539200

[5] Abdelmagid, S. M., Barbe, M. F., Hadjiargyrou, M., Owen, T. A., Razmpour, R., Rehman, S., Popoff, S. N., & Safadi, F. F. (2010). Temporal and spatial expression of osteoactivin during fracture repair. Journal of cellular biochemistry, 111(2), 295–309. https://doi.org/10.1002/jcb.22702

[6] Jiang, S. S., Chen, C. H., Tseng, K. Y., Tsai, F. Y., Wang, M. J., Chang, I. S., Lin, J. L., & Lin, S. (2011). Gene expression profiling suggests a pathological role of human bone marrow-derived mesenchymal stem cells in aging-related skeletal diseases. Aging, 3(7), 672–684. https://doi.org/10.18632/aging.100355

[7] Lo Sasso, G., Schlage, W. K., Boué, S., Veljkovic, E., Peitsch, M. C., & Hoeng, J. (2016). The Apoe(-/-) mouse model: a suitable model to study cardiovascular and respiratory diseases in the context of cigarette smoke exposure and harm reduction. Journal of translational medicine, 14(1), 146. https://doi.org/10.1186/s12967-016-0901-1

Christmas Fireplace

Happy Holidays from lifespan.io

Dear Friends,

As we close out the year and continue the holiday season, I want to take this opportunity to thank you for being part of our community at lifespan.io and helping to bring an end to the diseases of aging. 2021 has been another challenging year, but you did not let that stop you, and together, we have accomplished amazing things.

You crowdfunded the first large-scale placebo-controlled trial testing rapamycin on human longevity – raising more support than for any campaign we have launched in the past – and you helped transform our once-small website into the most-trafficked and respected outlet for aging research science, news, and advocacy in the world.

Your enduring support has also allowed us to branch out our media creation initiatives, support the birth of new organizations in the field dedicated to policy change and public engagement, and lay the groundwork for in-house research projects. Those of you who participated in the recent collaborative fundraising round via Gitcoin will have already seen the exciting projects we are planning for 2022 – all thanks to you.

As we enter this new year, I hope you will continue to see the value in our work and help us attain our next contribution goal – enabling us to keep delivering on the promise of ever-increasing engagement and public support for healthy life extension. If you are aware of other ways to help us in our mission, please feel free to let us know.

Finally, whether you can support us or not, I sincerely wish that you take good care of yourself this holiday season, stay healthy, and enjoy time with your family and friends. Inherent to the value proposition of life extension must be the notion that life itself is good and worth living – so please live it well and have a wonderful break, and I will see you in a brighter new year.

Thank you all.

Sincerely, Keith

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.
Two mice

Ichor Life Sciences Acquires Woodland Biosciences, Inc.

Woodland Biosciences, which studies metabolism and cancer, has joined the holdings of Ichor Life Sciences. Ichor intends to use Woodland’s expertise and research to increase the specializations of its pharmacological division. The full press release is provided here.

LaFayette, N.Y. — Ichor Life Sciences, a premium preclinical contract research organization offering services in discovery through pharmacology, announces it has formally completed the acquisition of Woodland Biosciences, Inc. The in vivo services for the study of metabolic diseases and oncology provided by the former Woodland Biosciences are now available through Ichor’s Pharmacology division.

A preclinical contract research organization, Woodland Biosciences was previously located on the campus of Tufts Veterinary Medicine School. Woodland’s R&D facilities have fully relocated from Tufts University to Ichor’s facilities in LaFayette, New York. Dr. Michael Briggs, the President and CSO of Woodland Biosciences, continues as part of Ichor’s scientific leadership in pharmacology. Dr. Briggs has deep expertise and experience in pharmacology and has worked on several preclinical and clinical programs in hepatitis, liver fibrosis and oncology, among others. Ichor Life Sciences’ clients and partners will continue to benefit from Dr. Briggs’ involvement in study designs and insights that can progress their preclinical programs.

“Woodland Biosciences’ capabilities in developing orthotopic and syngeneic models with a focus on liver and pancreatic cancers, along with models in NASH and other metabolic diseases, expands the specialization within our Ichor Pharmacology group,” says Dr. Kelsey Moody, PhD, MBA, Ichor Life Sciences’ CEO. “As we seek to continuously add to our portfolio of services and broaden our expertise, we plan to identify other opportunities for acquisitions in the months ahead.”

With these acquisitions and Ichor’s already deep expertise and capabilities in protein sciences and characterization, the company is well suited to provide a more comprehensive set of offerings from discovery through in vivo pharmacology to clients and partners in an innovative and entrepreneurial setting.

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.

Old and Young Mice

Senolytics Improve Muscle Regeneration Only in Old Animals

A new publication in Aging Cell has found divergent results between the post-injury muscle regeneration of young and old mice treated with senolytics [1].

Senescent cells: Friend or foe for muscle regeneration?

While it may not be obvious from the way senescent cells are often discussed in longevity circles, these cells play a critical role in tissue repair and wound healing. Senescent cells accumulate in the early stages after injury and then are reduced throughout the healing process [2,3]. However, despite an increased senescent cell population, regeneration from injury is impaired with aging. In muscle, a tissue with high regenerative potential, this results in more fibrotic scar tissue and both smaller and fewer muscle fibers after injury.

Other aspects of aging, such as stem cell exhaustion, may play a role in this deficit. However, there is also some evidence that the increase in senescent cells may be playing a direct role.

Senolytics are drugs that selectively target and kill senescent cells. They’ve been shown to extend healthspan and lifespan in various animal models. Impaired tissue healing is one potentially concerning side effect as these treatments begin human clinical trials. Additionally, whether senolytics might be a useful treatment to facilitate muscle regeneration after injury in the elderly is currently unknown.

A recent study at the University of Kentucky aimed to examine the effects of senescent cells on regeneration and repair, as well as the potential origins of these cells, in a mouse model of natural aging.

Do senolytics help or harm muscle regeneration?

Young (3-month-old) and aged (20-month-old) mice were used in this study. The drug combination dasatinib and quercetin (D+Q), the most well-studied senolytic treatment, was used to intermittently eliminate senescent cells in these mice. After 12 weeks, the mice were injected with barium chloride to simulate a muscular injury.

Prior to injury, physical function was assessed through multiple measurements. Old mice, when treated with D+Q, showed improvements compared to vehicle-treated controls, while young mice had higher levels of physical function than old mice but no changes between treatment groups. Interestingly, measurements of systemic inflammation were not decreased with D+Q treatment in young or old mice, which contradicts the results of previous studies.

SA-ß-gal staining (a measure of senescent cell burden) was very low after sham injury in both young and aged mice. In barium chloride-injured mice, SA-ß-gal staining after 7 days was dramatically elevated to similar levels, regardless of age or senolytic treatment status. SA-ß-gal staining decreased from 7 to 28 days in all groups, but was highest in aged mice not treated with senolytics.

Co-staining with CD11b showed that more than 90% of the senescent cells were macrophages at 7 days. RNAseq analysis suggested that by 14 days, the cells had begun to be cleared from the injury site in young mice, but in old mice, they had begun expressing more markers of senescence, such as the SASP and p21.

Analysis of the muscle tissue showed young mice to have greater regeneration at both 7 and 28 days than old mice. Average muscle fiber cross-sectional area was increased in older mice treated with D+Q by 28 days compared to untreated controls. However, the reverse was true for young mice, with reduced fiber cross-sectional area associated with D+Q treatment.

D+Q treatment also increased satellite cell infiltration in aged mice, with no effect on young mice. Further, D+Q increased muscle stem cell proliferation in age mice while reducing it in young mice.

Together, our data show that clearance of senescent cells is beneficial for muscle regeneration, but only in old mice. Most of the SA ß-Gal + cells in muscle from old mice following injury are CD11b+ macrophages, whereas in young mice, macrophages transition to a reparative phenotype to facilitate muscle regeneration (Jensen et al., 2020). By 14 days post-injury, macrophages in adult muscle express factors that facilitate satellite cell function and muscle fiber growth, whereas in old mice they express SASP markers. In addition to reducing the abundance of senescent cells in muscle, senolytics, particularly quercetin, may directly promote satellite cell proliferation to facilitate regeneration. Senolytics effectively reduce senescent cell burden, increase satellite cell abundance, reduce inflammatory gene expression, alter expression of ECM genes, and increase expression of genes in muscle metabolic pathways which may collectively augment muscle fiber regeneration, ultimately leading to increased fiber size and improved physical function. There are still many unknowns about the relationship among senescent cells, skeletal muscle regeneration, and sarcopenia, requiring further study.

Conclusion

Senescent cell burden is extremely low in muscle tissue, even with aging. This study showed that infiltrating macrophages after injury become senescent in older mice and impair the healing process. Senolytic treatment with D+Q improved muscle regeneration in old mice but hindered it in young mice.

The study has a few limitations, including its heavy reliance on SA-ß-Gal staining, which is a tricky measurement of senescence, and the uncertain applicability of barium chloride as an injury model. Clinical trials would be needed to confirm these findings in humans, but this study provides strong preclinical evidence that senolytics may be able to help muscle injuries in aged individuals even though they negatively impact the young.

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] Dungan, C.M. et al. Depletion of SA ß-Gal+ cells using senolytics improves muscle regeneration in old mice. Aging Cell (2021). https://doi.org/10.1111/acel.13528

[2] He, M. et al. Hsp90beta interacts with MDM2 to suppress p53-dpendent senescence during skeletal muscle regeneration. Aging Cell (2019). https://doi.org/10.1111/acel.13003

[3] Sarig, R. et al. Transient p53-mediated regenerative senescence in the injured heart. Circulation (2019). https://doi.org/10.1161/circulationaha.119.040125

Osteoarthritis

The Effects of Physical Activity on Frailty

A new study shows that even low levels of physical activity are very good for your muscles, bones, and joints, but exercising too much can potentially harm you [1].

The unholy trinity

Sarcopenia, osteoporosis, and osteoarthritis are the trio of age-related diseases that affect, respectively, muscles, bones, and joints. Sarcopenia is the progressive loss of skeletal muscle mass and strength. Osteoporosis is characterized by decreased bone density and deterioration of bone tissue. Osteoarthritis is the most common joint disorder that leads to degeneration of cartilage.

None of these diseases is deadly by itself, but they can drastically decrease the quality of life in old age. They are also known comorbidities for other diseases of aging – for instance, osteoarthritis is associated with a significantly higher risk of cardiovascular mortality [2]. The promise of geroscience is to extend healthspan along with lifespan so that people do not spend the last part of their lives in frailty and misery. To fulfill this promise, sarcopenia, osteoporosis, and ostreoarthritis must be addressed.

Quantifying activity

This new study uses the NHANES (National Health and Nutrition Examination Survey) database, a treasure trove of various health data collected from hundreds of thousands of Americans since the 1960s. Interestingly, although NHANES and some similar databases have been around for decades, today’s researchers can derive new insights from this old data thanks to advances in AI and computing power.

Previous studies have attempted to elucidate the relationship between the three diseases and physical activity, but the results were often inconclusive. This new study is different because it stratifies the dataset by four levels of physical activity: very low (VLPA), low (LPA), medium (MPA), and high (HPA). These levels were defined by the amount of MET minutes per week. MET stands for “metabolic equivalent of task”. 1 MET is equal to the amount of energy the body spends while at total rest, such as lying on a couch watching TV. Even sitting at a desk bumps up energy expenditure to 1.3 MET.

Here are some examples: both brisk walking and weight training with heavier weights score at 5 MET, bicycling on flat terrain is equivalent to 9 MET, and running is one of the most energy-consuming activities at 11.5 MET; 1 minute of running uses up 11.5 MET-min worth of energy.

In this study, VLPA was defined as getting less than 150 MET-min physical activity per week (on top of basic daily movement), LPA as 150-960 MET-min per week, MPA as 961-1800 MET-min per week, and HPA as more than 1800 MET-min per week. The researchers note that this is in accordance with the methodology used in many previous studies.

How much PA is too much?

Studying a representative subset of the NHANES database, the team established the overall prevalence of sarcopenia, osteoporosis, and osteoarthritis in 50+ year old Americans to be 16.9%, 4.9%, and 29.1%, respectively. The prevalence of the three diseases in the VLPA, LPA, MPA, and HPA groups was, respectively, 24.6%, 14.8%, 11.2%, and 9.1% for sarcopenia; 8.0%, 4.9%, 4.4%, and 2.7% for osteoporosis; and 35.1%, 27.0%, 25.3%, and 26.9% for osteoarthritis. After adjusting for multiple variables (age, sex, race/ethnicity, annual household income, educational level, smoking status, alcohol consumption, and BMI) the researchers arrived at this general picture:

Physical activity chart

Judging from these results, light physical activity is enough to significantly lower the risk of all three diseases. For sarcopenia, there is a steady decline in the odds ratio all the way from LPA to HPA, although the difference remains relatively small. For osteoporosis, there are no significant benefits when moving up from LPA to MPA, and HPA isn’t much better than LPA. Previous research shows similar association of PA levels with all-cause mortality: even low levels of physical activity bring significant benefits, while the difference between low and high levels is less pronounced [2].

Osteoarthritis, though, was the oddball among the three: while LPA and MPA significantly lower its risk, HPA brings it back almost to VLPA levels. This is probably because strenuous physical activity causes the wear and tear of cartilage. While at lower levels of physical activity, benefits for cartilage (such as decrease in inflammation) outweigh the drawbacks, high PA levels apparently do more harm than good.

Conclusion

There are two major takeaways from this new study. First, in terms of the risk of getting one or more of these degenerative diseases of aging, low levels of physical activity are much better than nothing and only slightly worse than higher levels. Second, for osteoarthritis, the most prevalent disease among the three, there is such a thing as too much physical activity.

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] Perez-Lasierra, J. L., Casajús, J. A., González-Agüero, A., & Moreno-Franco, B. (2021). Association of physical activity levels and prevalence of major degenerative diseases: Evidence from the national health and nutrition examination survey (NHANES) 1999–2018. Experimental Gerontology, 111656.

[2] Veronese, N., Cereda, E., Maggi, S., Luchini, C., Solmi, M., Smith, T., … & Stubbs, B. (2016, October). Osteoarthritis and mortality: a prospective cohort study and systematic review with meta-analysis. In Seminars in arthritis and rheumatism (Vol. 46, No. 2, pp. 160-167). WB Saunders.

[3] Mok, A., Khaw, K. T., Luben, R., Wareham, N., & Brage, S. (2019). Physical activity trajectories and mortality: population based cohort study. Bmj, 365.

EARD2021 Tina Woods

Tina Woods on a Longevity Ecosystem at EARD2021

At Ending Age-Related Diseases 2021, Elena Milova of lifespan.io interviewed Tina Woods on the development of a longevity ecosystem, the importance of language, and the social aspects of extending lifespans.

Script

Elena: Greetings to the participants of Ending Age-Related Diseases 2021. This conference brings together thought leaders and researchers working on rejuvenation biotechnology with the goal of extending healthy human life.

Introducing longevity interventions requires overcoming regulatory barriers, educating the medical community and discussing price tags. We all know that making treatments available doesn’t guarantee life extension, as there are other factors at play. The current pandemic uncovered many weaknesses in healthcare systems around the globe. This made it clear that if we want to increase life expectancy, then we must adopt a holistic approach.

These are the questions I’m discussing today with Tina Woods, CEO of Collider Health, an ecosystem architect working with organizations in both private and public sectors to accelerate innovation and achieve sustainable, transformational health systems. Tina is also the key driver of the All-Party Parliamentary Group for Longevity that is working with the UK government on the goal of adding five extra years of healthy, independent life for everyone by 2035.

Elena: Hello, Tina, thanks for joining us today.

Tina: Thank you so much for involving me. I was involved about a little over a year ago at one of your conferences. It’s really nice to be here again.

Let us discuss your work a little bit. What do you think is the most important achievement of the work of the All-Party Parliamentary Group for Longevity that you managed to achieve since its inception?

Policymakers and government always are in some ways going to be a step behind the sheer pace of change that’s going on in the scientific and technological world; we know that. You need to have some sympathy. Even for the ones who are in it, it’s difficult to keep pace. The one thing that we knew we had to do as part of this process of engaging government and policymakers is this whole process of opening eyes to all the stuff that’s going on, but seeing it from multiple perspectives.

We made a point of engaging with all the different perspectives that had a role to play in this sort of system change thinking. It’s about the scientific community, and obviously, the technology community, it’s about the business community, it’s about third sector, it’s about the NHS, but it’s also about the general public.

We spent quite a lot of time developing our group of experts and people that we felt should be at the table, and then going through this process of drilling down with all the different perspectives, then coming up and comparing and contrasting views. We’re very focused on this North Star goal of HLA +5: how do we achieve healthy life expectancy while minimizing health inequalities, and bear in mind this is right before COVID. Very quickly, within nine months, we got together around the table many times and managed to come out with nine recommendations, two of which are very, very advanced now, because we published our strategy for a healthier, longer life last February, so it’s right before COVID struck.

It was funny, because I just came back from Singapore, I was invited by the National Association of Medicine Global Healthy Longevity Program as a speaker. I remember when I hit the hotel room in Singapore, it was temperature checks, and I had a bag with the mask, and COVID had just started to get on the global radar.

When I got back, it was sort of like, oh, gosh, is the UK going to be affected by this, but we launched this strategy, and then had the support of our Secretary of State, and that got a lot of claim for how we approached it in terms of distilling down the nine key things we really need to get right from all these multiple perspectives.

Then COVID struck, and then we had a look, we could see when the data was first coming out. Our recommendations were even more compelling, because it really was focusing on this system change around health prevention, around addressing health inequalities. The two recommendations, I was really proud of that.

Just more recently, about three months ago, we published a follow-on report to say that life has moved on, the world has changed, what should be our short-term priorities? We contextualize, we try to be quite pragmatic about the short-term priorities.

We have a new government, a new prime minister, so we identified a handful of priorities that certainly in the next political cycle we should focus on, because there’s always that balancing act: the here and now, what we can do now, and the long term. We know that government and our institutions, they run on a fairly short timeframe, which I think is the big challenge, because they’re thinking five-year horizons.

When you’re thinking about health prevention, and certainly healthy longevity, life course stuff, you’re looking at really, really long time horizons, which will have a payback that takes a long, long time. That’s a massive, massive challenge.

Two of the things that we’re working on now is we’ve formed a Business for Health venture, which is looking at developing a business index to measure and incentivize the business contribution to health. The business community is a massive stakeholder in all of this, which has been really underrated from a public health and population health perspective.

We want to find a way to actually measure the role of business in health, and that’s in three key parameters, which is around employee health and well-being and the workforce health bit. We know that in the data, we will see that mental health and muscular skeletal conditions, as well as even things like headache and backache, things like that, these have massive impacts on workforce health and actually create big pressures on our healthcare systems to address.

That is an area through better health interventions at a workplace level could have a massive impact. Again, that one impact alone could have made a massive, massive difference.

The other level down, of course, is business impact in terms of products and services. There are many products and services, certainly, this is the work of my UK Research and Innovation work, the Healthy Aging challenge, we’re trying to stimulate that marketplace. We want to see more products and services to keep people healthy. As well, we want to engage people in new technologies, certainly what has come out through COVID, the COVID experience, how important communities are in generating local health resilience building.

We have various policy drivers at the moment, which are really trying to create much more localized public health intelligence systems, so that it’s not just centrally driven. I know the States is different, you’ve got your 50 states, it’s much more federated, but we’re moving in that direction in the UK context. We’re taking more of a place-based approach, recognizing that organizations, public health systems, but also businesses, social enterprises, local community organizations, they all have a massive role to play in terms of communities and regeneration of areas that have been left behind.

We have a whole program in the UK, leveling up health. The focus of our recent report is, how do you create a more equal playing field in the health of the local population. This has a massive role, because they employ local people.

We know that even things like good jobs, good wages, people in low-paid jobs tend to be much less healthy. It’s part of this whole health inequality situation. There’s a massive role in resilience building, and local community building, and the wider societal impact that business has a role to play in. We’re looking at all these and setting up a very simple way to standardize and measure the business impact of health.

We’re looking at specific industry sectors, I mentioned the food industry, so that’s very high on our map, we’re looking at housing, we know that housing has a massive impact. We need more better social housing to house people better, environments that are not overcrowded, have access to clean spaces, looking at transportation policies that people approach to walk more.

These are all things where government can have a huge role to play to create a better environment for people, better playgrounds for kids. To your point earlier, the legislation policy drivers to encourage better practice in the food case, but actually most fundamental, which I’m really excited about, is taking a leaf out of the climate change experience and bringing health into ESG mandates for investment, for significant long-term patient capital, into very bold, transformative approaches to health prevention and also care.

Because we need that, and we need much a longer-term horizon, which the investor community can do and be much more bold about the solutions. We’re creating a framework where we’re bringing health into ESG mandates. The business index is the precursor to that.

We kind of want to do what climate change has done, which is about 10 years ahead of us, just like the big investors and pension funds, they’re disinvesting away from coal andfossil fuels. We want to see the same thing happen in health, we want disinvestment, as we’ve already seen in tobacco, and even now, alcohol, we want to see that in health-harming industries, we want to disinvest from ultra-high processed foods.

We want to have a mentality where good, sustainable, responsible business investment is commercially attractive, as we’re seeing in the climate change space. Those sorts of things, we’re looking at in the business for health initiative that came out of the initial work, and I’m very involved with that. The other thing that is very significant dimension, which has more of a link to the science, technology, we’re creating an Open Life Data Framework. We deliberately avoided the word health because we want it to take the life course, the kind of life trajectories approach.

The massive focus at the moment with all of our policy and our life sciences industry, which is very strong in the UK, as you probably know, and biotech. Moving that away from just looking at the data in the sick care space because NHS and carrier data gets the lion’s share of attention in terms of policy investment, and looking at the wider determinants of health.

Of course, big tech are very, very conscious of all the data points in our lives, this is very much the heart of a lot of the work. I know the longevity scientists are looking at digital fingerprints and other biomarkers and all the rest of it. We’re trying to create an open innovation environment with the right governance mechanisms to open up much better data sharing and connectivity, much more awareness about what we can do to develop products and services to keep us healthy and to develop the insights to identify disadvantaged populations.

All these sorts of things will be unearthed through this Open Life Data Framework. We’re taking lessons from open banking, which has been very successful in opening up the innovation ecosystem for fin-tech, we want to take some of those lessons learned and bring it into this space. That’s a very busy project at the moment, we’re going to be publishing a framework in the next couple of months.

Private sector data is obviously very much a focus of this. That’s obviously what we’re looking at in the context of the business index that we’re developing within Business for Health. All of this, we’re aligning around another very interesting piece of work in the UK, the development of the ONS Health Index. The Office of National Statistics are developing a health index, which has taken an asset-based approach to health, which is around healthy people, healthy lives, and healthy places.

We’re trying to align all the thinking around a different view of health. Looking to other models that we’ve seen in New Zealand, for example, where they’re measuring the success of their nation on health and well-being and not just GDP. It’s a whole new way of thinking about what really matters to nations and societies. It’s looking at a systemic approach to global challenges and the opportunities to kind of address them through a different way of looking at the world, the problem, and also the solutions.

That sounds wonderful, you’re doing an impressive piece of work. This is something of incredible complexity, in my view. I will be very curious to learn, how did you manage to engage so many stakeholders at once to discuss the creation of those health and longevity ecosystems? Obviously, it’s been a success, and I really hope that this positive trend will proceed.

What’s your secret sauce when discussing these topics with all those stakeholders? Many of them can be actually pretty new to the field. How important is language?

For a start, you need a shared language that resonates with as many people as possible. What’s been really, really helpful, and it’s so important, is to have that mission statement that you can’t really argue with, that everyone can get behind. From that perspective, the UK goal, which is in our current manifesto commitment as well, how do we achieve healthy life expectancy or minimize health inequalities, that is something that is declared, it’s a North Star; you can bind everyone around that.

Now, how you get there, it may be that different stakeholders have different ways of seeing it. You can break down those those initial barriers by being very focused on that goal. That was really, really helpful. It was very interesting, because I think the whole language is really important.

I know I’ve spoken to many people about this idea of creating almost like a lexicon for longevity so that we can all be speaking the same language, because there’s so much confusion, what we mean by aging, ending aging, and what does longevity mean? What is healthy longevity? There’s a lot of confusion.

Having that simplicity in language, for example, I have noticed that because of the mission statement that we had, we’ve started talking because we’ve been much more positive about how we see it and how we can get to achieving this goal rather than seeing always as a problem. Already, the language has shifted from healthy aging towards the idea of healthy longevity, because it’s a more empowering language.

Unfortunately, aging is still tinged with negativity and the kind of ageism that does pervade a lot of the Western world, we still see aging in very negative terms. I think having a more positive language does open up the opportunity and the optimism around this. I think it is important. Ultimately, when you’re bringing such diverse stakeholders together, in the end, you have to have messages that will resonate with them so that they listen as a starting point, but then it’s about engaging, but then it’s about action.

Coming out of the pandemic, what I find really interesting is that we realize, for example, Westernized society completely driven by the old way of seeing things as GDP and profit-driven growth and all these sorts of things. I think we’re starting to see things differently. Now, what else is important to human beings to society, and that has come out really strongly as a result of the pandemic.

Language is important, the mission is important, but we’re getting more hard fact data about how closely health is connected to wealth and prosperity, because you can’t really argue with that, because that gives an incentive for the business community. It also gives an incentive to policymakers to focus on health and preventative health by seeing the sheer economics of it, and I only have to point to a few very gold standard reports.

McKinsey does some great work. They’ve put a cost on ill health and what you will gain. They’ve calculated addressing preventable health and the diseases that lead to poor health. You’re looking at a 10% uplift in GDP just by addressing all the chronic diseases that we are currently getting that could be prevented if we change our lifestyle. That’s massive.

My colleagues, Andrew Scott, and David Sinclair, they worked on a really interesting paper that was more specific to the aging question, ending aging, but they showed the sheer uplift that you will get by slowing the pace of aging and increasing life expectancy with good health. Their calculation was that it would add $38 trillion to the USA alone in terms of net gain.

These are massive figures. Once you get the economics showing what the cost of ill health is, we know it has a massive cost in terms of productivity and taking people out of work. They’re less economically productive, and they lose their will to live. You can see that with the opioid crisis, once people lose their purpose, and if they’re in ill health, they’re not able to work and contribute to society, it has these huge impacts. If they’re not able also to care for others, it’s a massive impact on the bottom line for society economically, and of course, the sheer social costs are just absolutely gigantic.

I think the economic arguments are becoming much stark and clear about why addressing our health through longevity science, but also, I have to say, the message that I would put forward is that we have to understand that ending aging and attacking the root of aging and understanding the chronic diseases of aging, that’s a very important part of it.

Such an important part is addressing the wider circumstance and why it is that we get trapped in ill health. That’s a much bigger question, which sometimes gets neglected, but I think does need to be very much part of the solution in terms of really delivering on this healthy longevity for all people.

Thank you. I think that’s a great piece of advice. I wanted to ask one more question about the language, though.

You’re in this field for several years; did you feel that there was a shift towards some more positive views on life extension, as opposed to just health extension lately in those meetups and groups and collaborations that you are setting up?

That’s a really interesting question. I think so. I think for those who are more in the know, and I’m talking for those who are more advanced in in the scientific community and longevity research in general, we can see that really the ultimate goal is to see this convergence of healthspan and lifespan. You want minimum morbidity to the end, and all these sorts of things.

What I would see though, outside of that, is much more use of healthspan and lifespan, just because there’s growing recognition of how important our health is. Also, just realizing the significant issues that we have with healthy life expectancy. The big policy focus in the UK has been very much on healthy life expectancy rather than life expectancy, because what we’ve seen is just the sheer magnitude of the gap between the years lived in good health between the poorest and the richest in society.

There’s a social question that has come up and has really put the focus on this whole issue around healthspan. From a policy perspective, I think it’s much easier to focus on, it’s more of an imperative than on life extension, because there’s no point in extending your life if you’re going to have a crappy life.

How do we address that question? At the same time, recognizing that a crap life is often linked to your health status, which is then linked to your other determinants of health. I think that’s where it has focused, certainly through the policy lens and the government lens, because in the end, the government priorities are going to be different from longevity scientists. That has to be understood.

It is about how do you create that shared language? I would say that shared language has converged around the healthspan aspect of it. As people get more aware of the gap, closing that gap and morbidity, because of course, most of our resources are spent on that final stage of life at the moment when we’re dealing with these very chronic, multi-complex, multi-morbidities.

I think it’s something like 15% of the NHS budget goes to those last two weeks of life, which is crazy, we need to shorten that, we need to focus on keeping us healthier. I just think it’s creating the right arguments for the stakeholders. Healthspan is very much more the focus in terms of the policy lexicon than lifespan.

One more question, then.

Taking into account all the enormous amount of information that you have collected during your work with the All-Party Parliamentary Group on Longevity, and everything that we learned from the situation with this pandemic, what do you think must be the key actions and key projects that policymakers should be focusing on?

I’ll talk from experience with me and the work that we’re doing in the UK context, but I think a lot of the messages and action points are similar for other Western nations and the US. The main takeaway is that we cannot separate health and wealth, it is totally connected. I think we need to keep on seeing health, and I think this has come out of the pandemic, as our greatest asset, and we need to protect, we need to do what we can to keep us, develop our health trajectory through all the technologies and scientific advances and also policy innovation that we have.

We do have to realize that we can’t really improve healthy longevity, healthy life expectancy for everyone without dealing with the health inequalities situation and the systemic inequalities. I think that is a really big message for all of us. When you’re so excited by the research, you have to keep going back to the reality of people’s lives day to day.

We also have to realize that so much of our health is shaped by factors outside of our control, which is why government policymakers do have to step in, it’s about the wider circumstance, the environment in which we thrive or don’t thrive, and access to new technologies.

The other thing which is worth mentioning is that there is something about as human beings that I don’t know if it can be answered by science, there’s that sense that drives us all forward. You’ll see that, it’s what drives our curiosity, and certainly the ambitions and interests and ingenuity of our scientific community. That’s really important.

It’s not our survival instinct, it’s not just hardwired in our genes like it is in animals. There’s something else that you can’t necessarily answer purely through science alone. That is also a really important part. It’s about creating a society where we all have really great lives, because we don’t want to live forever if we don’t have a good life. That’s a really difficult question to answer. Health and wealth is so fundamentally connected in terms of our future prosperity, so we need to focus on that.

That’s a great answer, thank you, I’m very satisfied with it. I personally think that opportunities that people have in terms of developing themselves, becoming better, getting education, pursuing professional careers, even by giving people those opportunities, we can achieve more, and I’m actually a big fan of the ideas of Jacque Fresco.

In this regard, the Venus Project actually has many great ideas and this is one of them. Give human beings an opportunity to properly develop, provide the resources for development, and you will see how this can dramatically change not only their life but also the life of our society at large, and how innovation can thrive much better, much faster in such an environment.

That’s such a nice way of leaving it. I was just going to say one final thing is this, our young people are out there, they have been so fantastic, and so generous to all of us older generations throughout the pandemic, and that spirit and that hope and that optimism and that kind of social consciousness, I think is so important and will really push us forward. We need to respect that, and we need to nurture that.

Wonderful, that’s a great roundup. Thank you for joining us, and I hope that you enjoy the rest of the conference. Thank you.

Thank you so much for everything and for involving me. Thank you so much.

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.
Obese mouse

A Vaccine for High Cholesterol Works in Mice

Researchers publishing in Cell Reports Medicine have discovered that a vaccine targeting angiopoietin-like protein 3 (ANGPTL3) alleviates dyslipidemia and improves outcomes in obese mice.

What is dyslipidemia?

Dyslipidemia is marked by having an excess of low-density lipoprotein (LDL) cholesterol, a lack of high-density lipoprotein (HDL) cholesterol, or an excess of triglycerides. It is strongly linked to cardiovascular disease (CVD), and cardiologists around the world recommend controlling dyslipidemia, especially LDL cholesterol [1], in order to minimize this risk.

The gene ANGPTL3, which is present in both humans and mice, was discovered to be knocked out in a mutant mouse with unusually low levels of triglycerides [2]. Another study found that inhibiting ANGPTL3 reduced the risk of CVD [3]. This spurred the researchers of this study to investigate whether ANGPTL3 could be directly targeted with a vaccine as a potential therapy against CVD.

A peptide-based vaccine

These researchers selected three different immune system targets (epitopes) of ANGPTL3, determined their peptides, and conjugated commercially available antibodies to these peptides. Referring to the resulting antibodies as E1, E2, and E3, the researchers then tested each of them in a mouse model of obesity.

E2 was not shown to be particularly effective, and E1 did not trigger a robust immune response. E3, however, was shown to significantly reduce LDL cholesterol and triglycerides while having a non-significant effect on HDL cholesterol. Fasting triglycerides were not significantly effected, but non-fasting triglycerides in obese mice immunized with E3 were shown to be approximately half those of the control group.

This metabolic data was reflected in the body composition of the animals. While total body weight was not affected, mice given E3 were shown to have less fatty livers compared to controls. The resulting pathologies were alleviated, and liver tissue was shown to have less of the inflammatory factors IL-6 and TNF-a.

Another mouse model of dyslipidemia was tested, and these mice, fed a high-cholesterol diet and given the E3 vaccine, were found to have less LDL and substantially lower non-fasting triglycerides than their untreated counterparts.

The team also tested for side effects. Concerned that the potential therapy might be toxic, the team wished to see if this approach was killing cells or causing fibrosis. Fortunately, neither issue was found in mice treated with the E3 peptide. The team also found that the ANGPTL3 vaccine remains effective for 30 weeks.

Conclusion

The phrase “Mice are not people” is commonly seen when discussing early-stage biomedical research, but this phrase bears special relevance here. ANGPTL3 is conserved between mice and humans, so it is logical to believe that this conservation is likely to allow this intervention to be effective in people, and clinical trials will determine whether or not this is actually the case.

However, people are not genetically modified mice being forced to eat an extremely high-cholesterol diet. While these mice were eating the equivalent of a common diet in the Western world, and many people do eat such a diet, it is well-known that this diet is linked to CVD in humans. Therefore, in the absence (or even the presence) of a clinically trialed ANGPTL3 vaccine, it is inadvisable to consume a diet that is more suitable for mouse models of obesity, dyslipidemia, and atherosclerosis.

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] Mach, F., Baigent, C., Catapano, A. L., Koskinas, K. C., Casula, M., Badimon, L., … & Wiklund, O. (2020). 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk: The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS). European heart journal, 41(1), 111-188.

[2] Koishi, R., Ando, Y., Ono, M., Shimamura, M., Yasumo, H., Fujiwara, T., … & Furukawa, H. (2002). Angptl3 regulates lipid metabolism in mice. Nature genetics, 30(2), 151-157.

[3] Dewey, F. E., Gusarova, V., Dunbar, R. L., O’Dushlaine, C., Schurmann, C., Gottesman, O., … & Baras, A. (2017). Genetic and pharmacologic inactivation of ANGPTL3 and cardiovascular disease. New England Journal of Medicine, 377(3), 211-221.

Raw hot peppers are a source of quercetin.

What Is Quercetin? A Summary of Quercetin

Found in many fruits and vegetables, quercetin may have some potential in the context of aging. Here, we take a look at this natural antioxidant and popular dietary supplement.

What is quercetin?

Quercetin is a natural flavonoid, which makes it part of a large family of water-soluble plant compounds. Flavonoids are not created by the body and are an important part of a healthy diet.

Albert Szent-Györgyi discovered flavonoids in 1936 while researching ways to treat scurvy. He won the Nobel Prize in 1937 for his “discoveries in connection with the biological combustion processes with special reference to vitamin C and the catalysis of fumaric acid”.

We have much to thank him for, especially his discovery of the flavonoids, particularly quercetin. Flavonoids were once known as vitamin P for permeability. This was because some flavonoids can influence the permeability of blood vessel walls.

What is quercetin used for?

Traditionally, people take quercetin because they believe it is effective in managing various issues, such as supporting the brain and immune system, slowing down skin aging, improving NAD+ levels, removing senescent cells as a senolytic, reducing blood pressure, and alleviating allergies.

What does quercetin do?

Quercetin is one of the most common antioxidants found in the diet and plays a key role in reducing damage to cells from free radicals. It may also have broader anti-inflammatory properties, as it reduces the activity of nuclear factor kappa B (NF-κB), a pro-inflammatory molecule. It also appears to reduce the inflammatory response of macrophages. Some research suggests that it is also a senolytic when combined with other drugs and may destroy senescent cells, which are another reason we age.

Foods rich in quercetin

Quercetin is present in a variety of fruits and vegetables.

Food Quercetin (mg per 100 g)
Raw capers 233.84
Raw hot/yellow peppers 50.73
Raw red onions 39.21
Cooked asparagus 15.16
Raw cranberries 14.84
Raw hot/green peppers 14.7
Raw lingonberries 13.3
Raw blueberries 7.67
Raw red leaf lettuce 7.61
Raw white onions 6.17
Tinned tomatoes 4.12
Red apples 3.86
Gala apples 3.8
Golden delicious apples 3.69
Raw broccoli 3.26
Raw sweet cherries 2.29
Black grapes 2.08
White grapes 1.12

Due to the variable nature of dietary sources, many people opt to use quercetin supplements to ensure that they are getting enough. A typical dietary supplement contains 500 mg of quercetin, which is many times higher than is typically present in the average diet.

Isoquercetin (also known as isoquercitrin) is related to quercetin and has better bioavailability [1]. It is harder to get than regular quercetin and may be more expensive, though smaller amounts are required, as it is around six times more potent.

Potential quercetin benefits

Some data suggests that quercetin intake may have a beneficial impact on health, and we have taken a look at some studies and potential benefits of quercetin.

Quercetin is an antioxidant

Quercetin has shown antioxidant properties by neutralizing and scavenging reactive oxygen and nitrogen species [2-3]. Our bodies produce free radicals as a byproduct of our mitochondria making energy, which is likely to be one of the reasons we age

It also has anti-bacterial [4-5], anti-inflammatory [6], and anti-carcinogenic [7-12] properties.

Quercetin supports efficient protein production

Quercetin has the ability to enhance proteolysis and maintain proteostasis [13-14]. Proteostasis ensures that proteins are created and folded correctly before use in the cell. The loss of proteostasis leads to misfolded proteins and is another reason we age.

Quercetin appears to support the brain and immune system

Animal studies with aged mice showed that quercetin improved general and spatial awareness [15]. The same mice also had an increased level of exploratory behavior, which is typically seen in younger mice.

Another study showed an improvement of the immune cells of artificially aged progeric mice [16]. While these mice are not an exact emulation of aging, they do provide useful data for studying aging.

Quercetin may slow down skin aging

Topical treatment increases the hydration and elasticity of the skin, reducing wrinkles [17]. The skin is also easy to access, unlike internal organs, making it an ideal target for anti-aging studies using flavonoids.

Quercetin has also shown efficacy in treating skin disorders such as dermatitis [18-20].

Quercetin may improve NAD+ levels

This compound reduces inflammation and increases NAD+ levels by reducing inflammatory factors such as CD38 [21-23]. NAD+ is in every cell, interacts with sirtuins to regulate metabolism, and plays a role in health and longevity. CD38 increases with age and consumes NAD+, making our metabolism increasingly dysfunctional.

Quercetin as a senolytic

As we age, increasing amounts of dysfunctional, non-dividing senescent cells accumulate. These damaged cells are normally removed by the immune system, but as we age, this system declines and more and more of these cells build up. Senescent cell accumulation is one of the reasons we age.

Senescent cells secrete a cocktail of pro-inflammatory signals known as the senescence-associated secretory phenotype (SASP)[24]. The SASP generates chronic levels of inflammation and an altered cell-to-cell signaling environment. This persistent inflammation, called “inflammaging”,  is believed to be one of the drivers of aging [25-26].

Senolytics are compounds that can induce senescent cells to enter apoptosis. Inducing this cellular self destruct could be a potential way of dealing with accumulated senescent cells.

Quercetin reduces inflammation by inhibiting some elements of the SASP. It can  also directly induce apoptosis when used in combination with other drugs to improve vascular health [27-28].

Quercetin may reduce blood pressure

This flavonoid has shown promise in reducing blood pressure, with some positive results for people with hypertension [29]. A detailed meta-analysis on quercetin and blood pressure was also conducted [30].

Quercetin may help with allergies

Quercetin has been shown to halt immune cells from releasing histamines, chemicals that trigger allergic reactions. This antihistamine effect may reduce the symptoms of allergies, such as runny nose, watery eyes, hives, and facial swelling.

Safety of quercetin and its side effects

No serious adverse effects from quercetin use have been reported. In fact, studies have shown that it can be taken safely at 500 mg twice daily for 12 weeks. Longer-term use and higher doses remain an unknown at this time. Some people may experience headaches, stomach aches, or tingling sensations if taking more than 1000 mg of quercetin in a day. As with all supplements, if you do experience adverse effects, you should cease taking it and consult your doctor.

Disclaimer

This article is only a very brief summary. It is not intended as an exhaustive guide and is based on the interpretation of research data, which is speculative by nature. This article is not a substitute for consulting your physician about which supplements may or may not be right for you. We do not endorse supplement use or any product or supplement vendor, and all discussion here is for scientific interest.

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] Paulke, A., Eckert, G.P., Schubert-Zsilavecz, M., & Wurglics, M. (2012). Isoquercitrin provides better bioavailability than quercetin: comparison of quercetin metabolites in body tissue and brain sections after six days administration of isoquercitrin and quercetin. Die Pharmazie-An International Journal of Pharmaceutical Sciences, 67(12), 991-996.

[2] Hanasaki, Y., Ogawa, S., Fukui, S. (1994). The correlation between active oxygens scavenging and antioxidative effects of flavonoids. Free Radical Biology and Medicine, 16(6), 845-850.

[3] Van Acker, S.A., et al. (1996). Structural aspects of antioxidant activity of flavonoids. Free Radical Biology and Medicine, 20(3), 331-342.

[4] Boots, A.W., Haenen, G.R., Bast, A. (2008). Health effects of quercetin:from antioxidant to nutraceutical.European Journal of Pharmacology, 585(2), 325-337.

[5] Cushnie, T.T., Lamb, A.J. (2005). Antimicrobial activity of flavonoids. International Journal of Antimicrobial Agents, 26(5), 343-356.

[6] Sen,G.,Biswas,D.,Ray,M.,Biswas,T.(2007). Albumin–quercetin combination offers a therapeutic advantage in the prevention of reduced survival of erythrocytes in visceral leishmaniasis. Blood Cells, Molecules, and Diseases, 39(3),245-254.

[7] Oršolić, N., et al. (2004). Immunomodulatory and antimetastatic action of propolis and related polyphenolic compounds. Journal of Ethnopharmacology, 94(2), 307-315.

[8] Gulati, N., et al. (2006). The antiproliferative effect of Quercetin in cancer cells is mediated via inhibition of the PI3K-Akt/PKB pathway. Anticancer Research, 26(2A), 1177-1181.

[9] Kuo, S.M. (1996). Antiproliferative potency of structurally distinct dietary flavonoids on human colon cancer cells. Cancer Letters, 110(1), 41-48.

[10] Landis‐Piwowar, K.R., Milacic, V., Dou, Q.P. (2008). Relationship between the methylation status of dietary flavonoids and their growth‐inhibitory and apoptosis‐inducing activities in human cancer cells.Journal of Cellular Biochemistry, 105(2), 514-523.

[11] Oršolić, N., et al. (2004). Immunomodulatory and antimetastatic action of propolis and related polyphenolic compounds.Journal of Ethnopharmacology, 94(2), 307-315.

[12] Zamin, L. L., et al. (2009). Resveratrol and quercetin cooperate to induce senescence‐like growth arrest in C6 rat glioma cells. Cancer Science, 100(9), 1655-1662.

[13] Trougakos, I.P., et al. (2003). Slowing down cellular aging in vitro. Modulating Aging and Longevity Kluwer Academic Publishers, 65-83.

[14] Chondrogianni, N., et al. (2010). Anti-ageing and rejuvenating effects of quercetin.Experimental Gerontology,45(10),763-771.

[15] Liu, J., Yu, H., Ning, X. (2006). Effect of quercetin on chronic enhancement of spatial learning and memory of mice.Science in China Series C:Life Sciences,49(6),583-590.

[16] Álvarez, P., et al. (2006). Improvement of leukocyte functions in prematurely aging mice after five weeks of diet supplementation with polyphenol-rich cereals. Nutrition, 22(9), 913-921.

[17] Nebus, J., Vassilatou, K., Philippou, L., Wallo, W. (2011). Clinical improvements in facial photoaged skin using a novel oak quercetin topical preparation.Journal of the American Academy of Dermatology, 64(2): AB73-AB73.

[18] Jung, M.K., Hur, D.Y., Song, S.B., Park, Y., Kim, T.S., Bang, S.I., … & Cho, D.H. (2010). Tannic acid and quercetin display a therapeutic effect in atopic dermatitis via suppression of angiogenesis and TARC expression in Nc/Nga mice. Journal of Investigative Dermatology, 130(5), 1459-1463.

[19] Weng, Z., Zhang, B., Asadi, S., Sismanopoulos, N., Butcher, A., Fu, X., … & Theoharides, T.C. (2012). Quercetin is more effective than cromolyn in blocking human mast cell cytokine release and inhibits contact dermatitis and photosensitivity in humans. PLoS One, 7(3), e33805.

[20] Karuppagounder, V., Arumugam, S., Thandavarayan, R.A., Sreedhar, R., Giridharan, V. V., & Watanabe, K. (2016). Molecular targets of quercetin with anti-inflammatory properties in atopic dermatitis. Drug discovery today, 21(4), 632-639.

[21] Escande, C., Nin,V., Price, N.L., Capellini, V., Gomes, A.P., Barbosa, M.T., … & Chini, E. N. (2013). Flavonoid Apigenin Is an Inhibitor of the NAD+ase CD38 Implications for Cellular NAD+Metabolism,Protein Acetylation, and Treatment of Metabolic Syndrome. Diabetes, 62(4), 1084-1093.

[22] Camacho-Pereira, J., Tarrago, M.G., Chini, C.C., Nin, V., Escande, C., Warner, G.M., … & Chini, E.N. (2016). CD38 dictates age-related NAD decline and mitochondrial dysfunction through an SIRT3-dependent mechanism. Cell metabolism, 23(6), 1127-1139.

[23] Schultz, M.B., & Sinclair, D.A. (2016). Why NAD+ Declines during Aging: It’s Destroyed. Cell metabolism,23(6),965-966.

[24] Coppé, J.P., Desprez, P.Y., Krtolica, A., & Campisi, J. (2010). The senescence-associated secretory phenotype: the dark side of tumor suppression. Annual review of pathology, 5, 99.

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

[26] van Deursen, J.M. (2014). The role of senescent cells in ageing. Nature, 509(7501), 439-446.

[27] Zhu, Y., Tchkonia, T., Pirtskhalava, T., Gower, A.C., Ding, H., Giorgadze, N., … & O’Hara, S.P. (2015). The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs.Aging cell,14(4),644-658.

[28] Roos, C.M., Zhang, B., Palmer, A.K., Ogrodnik, M.B., Pirtskhalava, T., Thalji, N.M., … & Zhu, Y. (2016). Chronic senolytic treatment alleviates established vasomotor dysfunction in aged or atherosclerotic mice. Aging Cell, 15(5), 973-977.

[29] Edwards, R.L., Lyon, T., Litwin, S.E., Rabovsky, A., Symons,J.D., & Jalili, T. (2007). Quercetin reduces blood pressure in hypertensive subjects. The Journal of nutrition, 137(11), 2405-2411.

[30] Serban, M.C., Sahebkar, A., Zanchetti, A., Mikhailidis, D.P., Howard, G., Antal, D., … & Lip, G.Y. (2016). Effects of Quercetin on Blood Pressure: A Systematic Review and Meta‐Analysis of Randomized Controlled Trials. Journal of the American Heart Association, 5(7), e002713.

Optimistic outlook

NewLimit: A New Biotech Working on Epigenetic Aging

Two investors, including a co-founder of Coinbase, have announced a new biotech venture that aims to solve aging by studying its epigenetic aspects.

New kid on the block

Long gone are the times when longevity biotech companies were scarce and poorly funded. Today, barely a week goes by without a major launch announcement, and more often than not, the founding team includes tech investors and crypto gurus.

A few days ago, in a blog post on their newly minted website, a duo of investors announced the launch of their company, NewLimit. These are Brian Armstrong, the co-founder and CEO of Coinbase, a leading crypto exchange, and Blake Byers, who most recently was a General Partner at Google Ventures, where he led investments in tech and biotech companies. He also holds a PhD in bioengineering from Stanford. The third person behind NewLimit is Alex Marson, Director of the Gladstone-UCSF Institute of Genomic Immunology and Professor of Medicine at University of California – San Francisco.

Betting on epigenetic reprogramming

NewLimit intends to use machine learning algorithms to study age-related epigenetic changes and develop therapies based on this knowledge. Certain changes in the human epigenome are indeed strongly correlated with aging, which forms the basis of methylation clocks, today’s golden standard for measuring biological age. Germline cells can naturally rewind their epigenome to a young state, which is how brand-new organisms are born from adult ones. Scientists have also learned to trigger this reset in somatic cells, creating induced pluripotent stem cells (iPSCs).

This is called epigenetic reprogramming, and NewLimit will not be the first company to bet on it. Many ventures have recognized the potential of this technology, including the secretive Google-founded behemoth Calico and the recently announced Altos Labs co-founded by Jeff Bezos and Yuri Milner.

This means that NewLimit will be facing some serious competition from the start. What is their secret weapon? “The most unique thing about NewLimit”, the founders write, “will not be the idea or the capital we have access to. Instead, it will be the people we hire and the culture we create.” According to Armstrong and Byers, NewLimit will be to other players what SpaceX is to NASA and Blue Origin.

Ambitious and optimistic 

The recent explosion of interest and investments in the longevity field has raised questions as to how sustainable this is. Even more than many other areas of medical research, geroscience is a marathon. We are only beginning to understand aging, and it takes a long time to prove the effectiveness of geroprotective interventions. Will the initial excitement eventually give way to despair, tanking the field?

It seems that the founders of NewLimit understand what lies ahead. They describe their goal as “incredibly ambitious” and one that “could take decades to achieve”. According to the website, one of the company’s values is “inherent optimism”, and NewLimit is going to need a lot of it.

Yet, NewLimit also plans to start generating revenue early on. The founders are unapologetic about building a for-profit company that “values products over papers”. It is unclear what kinds of products NewLimit intends to create, but the early ones might include consumer epigenetic tests, which already have a budding market.

The company has raised $105 million to date. Armstrong and Byers promise additional funding “upon reasonable progress” and do not expect money to be the limiting factor in the next few years.

They’re hiring

Their blog post also delves briefly into the ethical aspects of longevity, countering the two most popular arguments: that any addition to lifespan will inevitably be spent in age-related frailty and misery and that life-prolonging technologies will only benefit the rich. “Two years ago”, the founders write, “mRNA therapeutics packaged in liquid nano particles (LNPs) were a product only reserved for expensive gene therapies, but in 2021, over a billion people received an mRNA LNP to immunize them against COVID for less than $20 a dose.”

The fact that the Armstrong and Byers felt the need to explain themselves is telling: this would probably not happen if they were developing a cure for cancer or diabetes. Sadly, we still have to deal with various misconceptions about fighting aging and increasing longevity.

If you would like to join the effort, NewLimit is actively hiring “bright people who are earlier in their career and have not become too entrenched in traditional ways of thinking”. We encourage the intellectual rebels among us to pay attention.

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.
Elderly brain

Old Serum Shown to Kill Brain Stem Cells

A study published in Aging and Disease has shown how exposure to old serum causes hippocampal progenitor cells (HPCs), which form new neurons, to die.

Drawing and testing serum from living people

To begin their study, the researchers examined a middle-aged to old (MATO) cohort ranging in age from 52 to 89. This cohort consists of cognitively healthy individuals that were recruited as the control group in a different study. The researchers found that their chronological age was inversely correlated with brain volume as measured in multiple areas, including the hippocampus and the dentate gyrus.

When their serum was tested in vitro on a sample of HPCs, the researchers found weak correlations between neuroblast numbers and donor brain volume as well as DNA damage and donor brain volume.

The researchers also drew samples from younger people (average age of 27) and older people (average age of 77), then examined the effects of young and old serum on another cellular culture.

After determining the optimal amount of serum for testing, they found that a marker of apoptosis (cellular death), CC3, was approximately doubled in the cells that had received old serum. Additionally, the researchers found that cells cultured in older serum from people with very mild cognitive decline were found to have more immature neurons.

Reporting negative results

In this study, the researchers did something that is seldom shown in these sorts of studies: they reported many results that did not show statistical significance. For example, the proliferation marker Ki67 was not associated with old or young serum, as was expected from the results of parabiosis studies. Instead, the researchers investigated further, and found that this was most likely due to the use of antihypertensives; older people who took hypertensives were found to have significantly more Ki67 than those that did not.

Things like gender, education, and statin use were not shown to have very much effect on cellular readouts, and even chronological age within the old cohort was not shown to have a statistically significant effect. The researchers state that epidemological factors, natural variances that are expected in human studies, are responsible for the strong variance in the cellular readouts of cells exposed to their serum.

Changes to gene expression

Interestingly, most of the well-known aging-associated genes did not change their expression when cells were exposed to old serum. These included genes related to nutrient sensing, cellular senescence, intercellular communication, and inflammation. Telomerase seemed to be affected, but not to the level of statistical significance. The proteostasis-related enzyme UCHL1, which increases in aging mice, was shown to increase.

The expression of another gene, PARP1, was shown to decrease. While PARP1 serves a protective role in moderate amounts, it increases with age, and this accumulation is associated with age-related cognitive decline [1].

The researchers identified three more potentially important genes affected by the administration of old serum. TMEM149 is largely unexplored but is associated with chronological age, and it was increased with old serum, as is ENDOG. RFN126 decreased in response to old serum, and it is also related to proteostasis, cleaning up mislocated and misfolded proteins [2,3].

Conclusion

The researchers share the most critical point taken from their study as follows:

Importantly, we show that although key in vitro readouts following the cellular assay correlate with in vivo phenotypes such as hippocampal volumes and cognitive performance, they do not show association to chronological age. This supports the notion that a lifetime of contributing factors causes increased divergence between chronological and (neuro)biological age which leads to greater heterogeneity in older populations. Our findings support the here-described serum assay as a potential biomarker for neurobiological age, making it a valuble tool for studies investigating ageing and age-related conditions as well as lifestyle factors such as diet and exercise.

There is another question that can be taken from this study’s results, one that the researchers did not explore: Does antihypertensive medication have a positive impact on neurogenesis, as was suggested by the Ki67 results? If there is a positive association between antihypertensive medication and the development of new brain cells, one which is not simply attributable to the amelioration of the negative effects of hypertension, this may be a line of research worth exploring.

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] Mao, K., & Zhang, G. (2021). The role of PARP1 in neurodegenerative diseases and aging. The FEBS Journal.

[2] Rodrigo-Brenni, M. C., Gutierrez, E., & Hegde, R. S. (2014). Cytosolic quality control of mislocalized proteins requires RNF126 recruitment to Bag6. Molecular cell, 55(2), 227-237.

[3] Hu, X., Wang, L., Wang, Y., Ji, J., Li, J., Wang, Z., … & Zhang, Z. R. (2020). RNF126-mediated reubiquitination is required for proteasomal degradation of p97-extracted membrane proteins. Molecular Cell, 79(2), 320-331.

Michael and Eric With Logos

New Partnership Between Forever Healthy and Buck Institute

Yet another group has formed to advance early-stage biotechnology research. This time, the Forever Healthy Foundation, founded by Michael Greve, has formed a $5 million partnership with the Buck Institute in order to fund rejuvenation biotechnology.
The full press release is included here.

Forever Healthy and Buck Institute announce partnership to advance translational research in human rejuvenation

Michael Greve’s Forever Healthy Foundation commits $5 million to fund breakthrough science with strong potential for startup creation at the Buck —

Karlsruhe, Germany and Novato, CA, USA – December 15, 2021 – The Forever Healthy Foundation and the Buck Institute for Research on Aging today announced a new partnership to advance early-stage discoveries at the Institute that show promise to reverse physiologic aging in humans. The focus will be on cutting-edge research aimed at the repair of age-related damage at the cellular and molecular level, a hallmark of the aging process. Forever Healthy will commit up to $1 million per year for five years to drive this innovation. The funding aims to advance early-stage research with high translational potential in order to speed up the transition from lab to product.

German entrepreneur and longevity pioneer Michael Greve founded his humanitarian Forever Healthy initiative with the mission of accelerating the development of therapies to impede the aging process and the diseases that accompany it. This mission is in perfect alignment with the Buck Institute, the first independent biomedical facility in the world focused solely on the biology of aging.

Greve first established a relationship with Buck science in 2016 when he supported research in the labs of Judith Campisi, Ph.D., one of the leading global figures in the study of cellular senescence, and Julie Andersen, Ph.D., a prominent researcher working to find new therapeutic interventions for neurodegenerative diseases such as Alzheimer’s and Parkinson’s. “I am really impressed with Buck science,” said Greve, “and view this enhanced partnership as the next step in translating research on aging into preventative therapies for people everywhere.”

“We are most appreciative of Michael’s generosity and vision,” said Eric Verdin, MD, President, and CEO of the Buck Institute. “It is an incredible and exciting time for our field, and we are delighted to be working with Forever Healthy as we move toward translational research.”

About Forever Healthy

Forever Healthy is Michael Greve’s humanitarian initiative with the mission of enabling people to vastly extend their healthy lifespan. Forever Healthy’s projects include evaluation of new rejuvenation therapies, evidenced-based curation of the world’s cutting-edge medical knowledge, funding translational research on the root causes of aging, and hosting the annual Undoing Aging Conference. Greve’s venture capital firm, Kizoo, which provides mentoring, seed and follow-on financing for rejuvenation biotech startups, is also part of the initiative. So far, Kizoo has funded fourteen startups turning research on the root causes of aging into therapies for human application.

Learn more at: https://www.forever-healthy.org

About the Buck Institute

Our success will ultimately change healthcare. At the Buck, we aim to end the threat of age-related diseases for this and future generations by bringing together the most capable and passionate scientists from a broad range of disciplines to identify and impede the ways in which we age. An independent, nonprofit institution, our goal is to increase human healthspan or the healthy years of life. Globally recognized as the pioneer and leader in efforts to target aging, the number one risk factor serious diseases including Alzheimer’s, Parkinson’s, cancer, macular degeneration, heart disease, and diabetes, the Buck wants to help people live better longer.

Learn more at: https://buckinstitute.org

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.
Plant-Based Diet

Plant-Based Diet Linked To Reduced Leaky Gut Syndrome

The MaPLE trial in Italy investigated whether or not increasing fruits and vegetables decreases leaky gut syndrome [1].

Background

This study examines increased intestinal permeability (leaky gut) in adults 60 years and older [1].  Age has been reported to be a risk factor for increased intestinal permeability over the age of 50 [2]. The authors of this study hypothesized that consuming a plant-rich, and therefore polyphenol-rich, diet would induce serum metabolomic changes associated with better intestinal permeability through gut bacteria.

Methods

This randomized, controlled trial included eight weeks of eating three portions of polyphenol-rich foods daily, which was followed by eight weeks of being back on a regular diet in a long-term care center. There was an eight-week break between each diet.

The researchers evaluated increased intestinal permeability by measuring serum zonulin levels in 51 participants after an overnight fast. Zonulin is a human protein that is known to be involved in regulating tight junctions in the gut, and higher zonulin levels reflect worse intestinal permeability. A leaky gut may contribute to inflammaging, and having a sustained high zonulin level predisposes people to additional health issues.

Elevated zonulin has been reported in many research studies across different ages and disease conditions, including, but not limited to, celiac disease, type 1 diabetes, pre-diabetes, type 2 diabetes, rheumatoid arthritis, multiple sclerosis, obesity, polycystic ovary syndrome, and irritable bowel syndrome [3,4].

The gut microbiota results were determined by analyzing stool samples. They also collected anthropometric data, blood pressure, and measures of functional, metabolic, inflammation, vascular, and oxidative stress markers, and they used specialized software to analyze three food records per day per person. They estimated the polyphenol content of each food as well using the Phenol Explorer database.

Results

This study showed reduced blood pressure in both men and women following an 8-week polyphenol-rich diet. This diet contained approximately 579 more milligrams of polyphenols in a day than the regular control diet [5]. Polyphenol-rich foods, such as cocoa, green tea and berries, led to significant reductions in zonulin.

This research also explains the secondary outcomes of the initial cohort. The polyphenol-rich diet was significantly lower in animal and plant protein, total fat, monounsaturated fatty acids, polyunsaturated fatty acids, total omega-6 fatty acid, calcium, and iron than the control diet. Stool bacterial communities did not vary in comparison between the diets.

Using a liquid chromatography technique, the researchers determined that seven of the metabolites were significantly increased while three metabolites significantly decreased. The increased metabolites included catechol sulfate, hippuric acid, and 2-methyl pyrogallol sulfate, which are markers of polyphenols being digested in the stomach that then undergo additional metabolism in the liver [6,7,8]. The metabolites 3-methylxanthine, 7-methylxanthine, theobromine, and HPPA-S were also increased after the 8-week polyphenol-rich diet. Lower levels of the metabolic product deoxycarnitine were correlated with a less leaky gut [9], and the researchers reported lower amounts of deoxycarnitine after the polyphenol-rich diet ended.

A heatmap showed the significant correlations. Serum zonulin and serum metabolites were significantly altered by the polyphenol-rich diet interventions and many of the nutrients that the researchers measured.

The researchers also investigated correlations between serum metabolome and gut microbiota. Notably, theobromine, a compound found primarily in cocoa, showed the most statistically significant correlations. In prior research, theobromine has been associated with beneficial gut bacteria that converts plant ligins to the compound enterolactone [10].

In summary, this multi-omics study shows that age, the baseline level of zonulin, and changes in the abundance of the bacteria porphyromonadaceae are primarily responsible for the total level of zolunin.

Conclusion

The major limitation of this study is that it does not prove a causal relationship between a polyphenol-rich diet, zolunin, and leaky gut. There are likely other food components present in this diet that may oppose or promote each other’s effects.

Other polyphenols have been associated with higher expression of tight gut proteins in the stomach, so increasing polyphenol rich-foods in diet may help leaky gut syndrome. Often, diet recommendations may include an anti-inflammatory diet, which includes foods that increase positive gut bacteria and excludes foods that cause bloating, constipation and diarrhea. Leaky gut may also be triggered by lifestyle factors, such as alcohol interacting with tight gut junction proteins [11,12]. There is currently no clear dietary treatment for leaky gut, so evidence-based research is needed to develop a personalized approach.

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] Peron, G., Gargari, G., Meroño, T., Miñarro, A., Lozano, E. V., Escuder, P. C., González-Domínguez, R., Hidalgo-Liberona, N., Del Bo’, C., Bernardi, S., Kroon, P. A., Carrieri, B., Cherubini, A., Riso, P., Guglielmetti, S., & Andrés-Lacueva, C. (2021). Crosstalk among intestinal barrier, gut microbiota and serum metabolome after a polyphenol-rich diet in older subjects with “leaky gut”: The MaPLE trial. Clinical nutrition (Edinburgh, Scotland), 40(10), 5288–5297. https://doi.org/10.1016/j.clnu.2021.08.027

[2] Nicoletti C. (2015). Age-associated changes of the intestinal epithelial barrier: local and systemic implications. Expert review of gastroenterology & hepatology, 9(12), 1467–1469. https://doi.org/10.1586/17474124.2015.1092872

[3] Sturgeon, C., & Fasano, A. (2016). Zonulin, a regulator of epithelial and endothelial barrier functions, and its involvement in chronic inflammatory diseases. Tissue barriers, 4(4), e1251384. https://doi.org/10.1080/21688370.2016.1251384

[4] Ciccia, F., Guggino, G., Rizzo, A., Alessandro, R., Luchetti, M. M., Milling, S., Saieva, L., Cypers, H., Stampone, T., Di Benedetto, P., Gabrielli, A., Fasano, A., Elewaut, D., & Triolo, G. (2017). Dysbiosis and zonulin upregulation alter gut epithelial and vascular barriers in patients with ankylosing spondylitis. Annals of the rheumatic diseases, 76(6), 1123–1132. https://doi.org/10.1136/annrheumdis-2016-210000

[5] Del Bo’, C., Bernardi, S., Cherubini, A., Porrini, M., Gargari, G., Hidalgo-Liberona, N., González-Domínguez, R., Zamora-Ros, R., Peron, G., Marino, M., Gigliotti, L., Winterbone, M. S., Kirkup, B., Kroon, P. A., Andres-Lacueva, C., Guglielmetti, S., & Riso, P. (2021). A polyphenol-rich dietary pattern improves intestinal permeability, evaluated as serum zonulin levels, in older subjects: The MaPLE randomised controlled trial. Clinical nutrition (Edinburgh, Scotland), 40(5), 3006–3018. https://doi.org/10.1016/j.clnu.2020.12.014

[6] Rechner, A. R., Kuhnle, G., Hu, H., Roedig-Penman, A., van den Braak, M. H., Moore, K. P., & Rice-Evans, C. A. (2002). The metabolism of dietary polyphenols and the relevance to circulating levels of conjugated metabolites. Free radical research, 36(11), 1229–1241. https://doi.org/10.1080/246-1071576021000016472

[7] Pimpão, R. C., Ventura, M. R., Ferreira, R. B., Williamson, G., & Santos, C. N. (2015). Phenolic sulfates as new and highly abundant metabolites in human plasma after ingestion of a mixed berry fruit purée. The British journal of nutrition, 113(3), 454–463. https://doi.org/10.1017/S0007114514003511

[8] Pasinetti, G. M., Singh, R., Westfall, S., Herman, F., Faith, J., & Ho, L. (2018). The Role of the Gut Microbiota in the Metabolism of Polyphenols as Characterized by Gnotobiotic Mice. Journal of Alzheimer’s disease : JAD, 63(2), 409–421. https://doi.org/10.3233/JAD-171151

[9] Semba, R. D., Trehan, I., Li, X., Moaddel, R., Ordiz, M. I., Maleta, K. M., Kraemer, K., Shardell, M., Ferrucci, L., & Manary, M. (2017). Environmental Enteric Dysfunction is Associated with Carnitine Deficiency and Altered Fatty Acid Oxidation. EBioMedicine, 17, 57–66. https://doi.org/10.1016/j.ebiom.2017.01.026

[10] Cardona, F., Andrés-Lacueva, C., Tulipani, S., Tinahones, F. J., & Queipo-Ortuño, M. I. (2013). Benefits of polyphenols on gut microbiota and implications in human health. The Journal of nutritional biochemistry, 24(8), 1415–1422. https://doi.org/10.1016/j.jnutbio.2013.05.001

[11] Wang, Y., Tong, J., Chang, B., Wang, B., Zhang, D., & Wang, B. (2014). Effects of alcohol on intestinal epithelial barrier permeability and expression of tight junction-associated proteins. Molecular medicine reports, 9(6), 2352–2356. https://doi.org/10.3892/mmr.2014.2126

[12] Wang, Y., Tong, J., Chang, B., Wang, B., Zhang, D., & Wang, B. (2014). Effects of alcohol on intestinal epithelial barrier permeability and expression of tight junction-associated proteins. Molecular medicine reports, 9(6), 2352–2356. https://doi.org/10.3892/mmr.2014.2126

Stethoscope Clock

Epigenetic Clock Shows Association With Cardiovascular Aging

A new study published in Mechanisms of Ageing and Development has found correlations between cardiovascular aging and a measure of epigenetic age acceleration [1].

Can epigenetic clocks predict cardiovascular disease?

One way researchers test the validity and usefulness of epigenetic clocks is to compare their outputs to other measures of biological aging, such as the occurrence of age-related diseases [2]. Cardiovascular disease is one of the largest causes of death around the world, and age is its primary risk factor. Despite this, research findings have been inconsistent when studying the relationships between measures of epigenetic age and cardiovascular disease. Many high-profile studies have reported a range of associations between the two, but others have shown no association at all [3].

Measuring epigenetic aging and cardiovascular disease

In this study, scientists from Charité Medical University in Berlin utilized the Berlin Aging Study II [4], which aims to explore factors that impact aging both positively and negatively. Its participants reside in Berlin, and the sub-group used in this study consisted of people between ages 60 and 84 (n=1671).

Participants degree of cardiovascular disease was measured by two common composite scores, the LS7 [5] and FRS [6].

An epigenetic clock that was modified from Vidal-Bralo [7] and uses only 7 CpG methylation sites [6] was used in this study. This clock is much simpler compared to the more popular Horvath (353 CpGs) and Hannum (71 CpGs) clocks.

For this study, the primary variable of interest from the epigenetic clock was epigenetic age acceleration. This is typically defined as the difference between biological age, as estimated by the epigenetic clock, and chronological age. However, the authors also accounted for leukocyte cell distribution (monocytes, lymphocytes, etc.) in addition to chronological age in this analysis. Previous studies have shown that this may be a key variable, as epigenetic measures are often made from leukocytes [8], including the dataset in this study.

LS7 and FRS are associated with epigenetic age acceleration

148 participants showed clinical signs of cardiovascular diseases, but many more showed a variety of risk factors, including high blood pressure, diabetes, high cholesterol, smoking, etc.

Epigenetic age acceleration was correlated with both LS7 and FRS for both men and women, with the absolute value of the correlation coefficient (r) ranging between 0.049 and 0.084. While this is considered a weak correlation, epigenetic age acceleration was more predictive than chronological age, which had a correlation coefficient of r = 0.007. When a linear regression model was applied, the association between epigenetic age acceleration and both LS7 and FRS was statistically significant (p<0.05).

Looking at individual components within both scores, physical activity was the most associated with epigenetic age acceleration for LS7 relative to diet, BMI, HbA1c, total cholesterol, smoking, and blood pressure. Similarly, for the FRS items, HDL cholesterol and total cholesterol were the primary drivers of its association with epigenetic age acceleration, with slightly less impact from chronological age, diabetes, systolic blood pressure, and smoking.

In conclusion, our results provide evidence of a weak association of the epigenetic clock (DNAm age acceleration) with cardiovascular health in the BASE-II cohort. We were able to confirm our initial hypothesis that more favorable results in the Life’s simple 7 (LS7) and the Framingham Risk Score (FRS) would be associated with a lower DNAm age acceleration. The DNAm age acceleration of participants with more favorable scores in the well-established instruments FRS and LS7 resulted to be lower compared to participants with less favorable score results. Moreover, we found our hypothesis that the LS7 may be associated more strongly with DNAm age acceleration than the FRS because it includes physical activity and diet at least partially confirmed. Physical activity resulted to be the driving force in the association between DNAm age acceleration and the Life’s simple 7. As expected, women displayed more favorable results in the CVH scores and had significantly lower epigenetic age acceleration than men. The above findings add to the growing body of evidence supporting the epigenetic clock´s potential as a biomarker of aging in the context of CVH and lifestyle factors.

Conclusion

This study is the first to compare LS7 and FRS with epigenetic age acceleration. Different study population datasets, epigenetic clocks, and measurements of cardiovascular disease have been examined in previous studies. While this study contributes to the muddled findings of previous work to a certain extent, it also suggests that some components of cardiovascular disease (such as physical activity, HDL cholesterol, and total cholesterol) may be more related to measures of epigenetic age acceleration than others. Epigenetic clocks are still relatively new to longevity research and will likely require many more studies such as this one to sort out their optimal parameters, which components of aging they are associated with, and why.

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] Lemke, E. et al. Cardiovascular health is associated with the epigenetic clock in the Berlin Aging Study II (BASE-II). Mechanisms of Ageing and Development (2021). https://doi.org/10.1016/j.mad.2021.111616

[2] Ferrucci, L. et al. Measuring biological aging in humans: A quest. Aging Cell (2020). https://doi.org/10.1111/acel.13080

[3] Lind, L. et al. Methylation-based estimated biological age and cardiovascular disease. Eur J Clin Invest (2018). https://doi.org/10.1111/eci.12872

[4] Bertram, L. et al. Cohort profile: The Berlin Aging Study II (BASE-II). Int J Epidemiol (2014). https://doi.org/10.1093/ije/dyt018

[5] Konig, M. et al. Historical trends in modifiable indicators of cardiovascular health and self-rated health among older adults: Cohort differences over 20 years between the Berlin Aging Study (BASE) and the Berlin Aging Study II (BASE-II). PLoS One (2018). https://doi.org/10.1371/journal.pone.0191699

[6] D’Agostino, R.B. Sr. et al. General cardiovascular risk profile for use in primary care: the Framingham Heart Study. Circulation (2008). https://doi.org/10.1161/circulationaha.107.699579

[7] Vidal-Bralo, L., Y. Lopez-Golan, and A. Gonzalez. Corrigendum: Simplified Assay for Epigenetic Age Estimation in Whole Blood of Adults. Front Genet (2017). https://doi.org/10.3389/fgene.2017.00051

[8] Quach, A.L. et al. Epigenetic clock analysis of diet, exercise, education, and lifestyle factors. Aging (Albany NY) (2017). https://doi.org/10.18632/aging.101168

Grape seeds

A Grape seed Extract Slows Aging In Mice

Studying grape seed extract, scientists have discovered a new senomorphic compound that enhances chemotherapy and prolongs lifespan and healthspan in mice [1].

Nature’s drugstore

Many drugs have come to us from the world of plants, including promising geroprotective molecules such as resveratrol. However, identifying specific components of plant extracts that exert positive effects can be challenging.

In this new study, the researchers started by screening a library of 46 plant-derived compounds for their senolytic potential – that is, the ability to remove senescent cells.

The researchers treated cells in vitro with a senescence-inducing compound and then applied the chemicals from the library to ascertain their senolytic effects. They also used several known senolytics as controls. The list of compounds that had exhibited a senolytic potential included the well-known curcumin and fisetin, but the researchers decided to focus on grape seed extract (GSE) due to both the magnitude of its effects on senescent cells and its relative paucity of research.

Both senomorphic and senolytic

In a series of experiments, the researchers confirmed that GSE effectively reduces SASP secretion, but in moderate doses, this was not accompanied by senescent cells being wiped out. According to the researchers, this effect is more senomorphic in nature, which means that it preserves senescent cells but alleviates harmful aspects of their phenotype [2]. The senomorphic approach has been gaining popularity recently because senescent cells are not always bad, and their elimination might be ill-advised in certain conditions.

Still, the researchers also tested GSE’s senolytic abilities and found them to be just as impressive. At higher concentrations, GSE eliminated up to 80% of senescent cells without affecting the viability of normal cells.

GSE consists of many different molecules, so which one or ones are responsible for its senolytic action? A component called procyanidin C1 (PCC1) that belongs to the flavonoid family caught the researchers’ attention due to its known ability to induce DNA damage. The scientists repeated the experiments with only PCC1 and found that its effect was very similar to that of GSE. Other GSE components did not exhibit senolytic activity – or at least, not at the same scale as PCC1.

Senolytics and cancer

The researchers then ran a series of experiments in vivo on cancerous tumors in mice. It is known that senescent cells are instrumental in preventing cancer in its early stages but might actually team up with it in later ones [3]. For instance, they can contribute to a tumor’s resistance to chemotherapy [4]. What’s worse, radiotheraphy and chemotherapy themselves induce cellular senescence by inflicting stress on healthy cells.

The researchers induced tumors in mice and then treated them either with a chemotherapeutic known as mitoxantrone, PCC1, or with the mitoxantrone-PCC1 duo. Unsurprisingly, mitoxantrone administration led not just to an anti-tumor effect but also to the appearance of numerous senescent cells in the tumor tissue. However, PCC1 eliminated most of those cells. As a result, the combination treatment remarkably enhanced tumor regression (55.2% reduction in tumor size compared to mitoxantrone alone).

Mice who were receiving the mitoxantrone-PCCC1 combo survived 1.5 times longer than the group treated with mitoxantrone alone. To be sure, PCC1 without mitoxantrone did not have a significant effect on survivability: after all, PCC1 is just a sidekick that clears senescent cells, making the job of the chemotherapeutic agent easier.

Genuine life extension

The researchers then performed additional in vivo experiments to assess PCC1’s ability to attenuate senescence-related physical dysfunction. It is known that even a small number of senescent cells can affect organismal health, including in young organisms. The researchers implanted senescent cells into young mice, which led to a decline in their physical abilities (maximum walking speed, hanging endurance, and grip strength), but this decline was largely reversed by PCC1 treatment.

Finally, to examine the effect of PCC1 on organismal aging, the researchers tested it on a bunch of naturally aging wild type mice. By the age of two years (or around 75 in human years), cellular senescence ran rampant in those mice. Bi-weekly PCC1 treatment that lasted about four months eliminated a large percentage of senescent cells and led to an increase in physical function and longevity. Treated mice lived for almost 10% longer, and their median post-treatment lifespan increased by a whopping 64%.

Lifespan of mice on a senomorphic compound

Conclusion

In this study, the researchers have identified a new powerful plant-derived senolytic compound and conducted extensive experiments to learn how it helps fight cancer and prolongs lifespan and healthspan in mice. By doing so, they also provided additional support to the theory that senolytics can effectively slow aging, even when administered later in life.

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Literature

[1] Xu, Q., Fu, Q., Li, Z., Liu, H., Wang, Y., Lin, X., … & Sun, Y. (2021). The flavonoid procyanidin C1 has senotherapeutic activity and increases lifespan in mice. Nature Metabolism, 1-21.

[2] Zhu, X. Y., & Lerman, L. O. (2022). Senomorphic, senolytic, and rejuvenation therapies. In Regenerative Nephrology (pp. 405-417). Academic Press.

[3] Wyld, L., Bellantuono, I., Tchkonia, T., Morgan, J., Turner, O., Foss, F., … & Kirkland, J. L. (2020). Senescence and cancer: A review of clinical implications of senescence and senotherapies. Cancers, 12(8), 2134.

[4] Georgilis, A., & Gil, J. (2016). Controlling secretion to limit chemoresistance. Genes & development, 30(16), 1791-1792.

Olives

Olive Derivative Fights Epigenetic Kidney Aging

Researchers publishing in Aging Cell have discovered how and why oleuropein (OLP), a polyphenol derived from olives, ameliorates epigenetic kidney aging.

Upregulation and downregulation

Like nearly everything in biology, this specific part of kidney aging results from a chain of events. Here, the researchers show that DNA methyltransferases (DNMTs), which methylate and thereby epigenetically suppress genes [1], are responsible for suppressing NRF2 and KLOTHO, two beneficial and antioxidant genes known to mitigate multiple aspects of aging [2,3], in the kidneys. This aspect of aging is suppressing the genes that fight other aspects of aging.

As the first step in demonstrating this, the researchers examined the kidneys of both naturally aged mice and mice that were artificially aged through the application of D-galactose (D-gal). In both sets of mice, KLOTHO and NRF2 were significantly downregulated. Fibrosis went up, macrophage infiltration went up, and the senescence marker SA-ß-gal was increased as well.

The researchers also analyzed DNMT levels in both sets of mice. Unsurprisingly, DMNTs and DNA methylation were elevated in both mouse models of aging. At 7 months in wild-type mice, DMNT1 was shown to be elevated; at 16 months, and further at 25 months, DMNT3a and DMNT3b were elevated as well. This was directly correlated with the decline in NRF2 and KLOTHO expression, whose gene sites were found to be heavily methylated.

Suppressing the suppressor

To determine a causal relationship between methylation and gene expression, and hopefully combat this aging, the researchers examined the effects of the synthetic drug SGI-1027 along with the potentially less cytotoxic OLP.

Both treatments worked as intended. Renal (kidney) DNA methylation was significantly decreased with both interventions, more so for SGI-1027 than OLP. Mice given both D-gal and OLP were shown to have only slightly higher amounts of DMNTs than control mice. The suppressor had been, itself, suppressed.

The researchers confirmed their findings by examining the downstream effects. As expected, NRF2 and KLOTHO expression were restored. The associated markers of kidney function were also restored: macrophage infiltration was largely absent; levels of blood urea nitrogen and creatinine, two markers of kidney function, became closer to those of control mice; fibrosis was significantly reduced. As a whole, the intervention was shown to be highly effective in this model.

The researchers then broke this causal chain in multiple places to prove its existence. First, they showed that using dimethyloxallyl glycine to suppress the effects of SGI-1027 and OLP on DMNT (suppressing the suppressor of the suppressor) prevented the positive changes. They also used silencing RNA to render mice deficient in KLOTHO, and these mice did not benefit from this treatment.

Conclusion

As usual, while the results were stark and highly significant, this was a mouse study. While a human study is much more expensive and involved, the significance of these results suggests that a clinical trial of OLP’s effects on kidney function might be the first step in bringing a potentially effective treatment to market, alleviating the suffering of a great many people suffering from renal 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] Maunakea, A. K., Nagarajan, R. P., Bilenky, M., Ballinger, T. J., D’Souza, C., Fouse, S. D., … & Costello, J. F. (2010). Conserved role of intragenic DNA methylation in regulating alternative promoters. Nature, 466(7303), 253-257.

[2] Silva-Palacios, A., Ostolga-Chavarría, M., Zazueta, C., & Königsberg, M. (2018). Nrf2: Molecular and epigenetic regulation during aging. Ageing research reviews, 47, 31-40.

[3] Kim, S. J., Cheresh, P., Eren, M., Jablonski, R. P., Yeldandi, A., Ridge, K. M., … & Kamp, D. W. (2017). Klotho, an antiaging molecule, attenuates oxidant-induced alveolar epithelial cell mtDNA damage and apoptosis. American Journal of Physiology-Lung Cellular and Molecular Physiology, 313(1), L16-L26.