May 2023 Longevity Research Newsletter

Introduction

Welcome to this month's edition of our newsletter, where we delve into the fascinating realm of gerontology - the scientific study of ageing - which has increasingly become a pivotal area of research, given the world's ageing population. This discipline, which explores the biological, psychological, and sociological aspects of ageing, has led to significant advances in understanding age-related diseases and interventions. Key to these advancements are human trials and interventions, turning laboratory findings into strategies that can enrich our lives as we age. This month, we are thrilled to feature an exclusive interview with renowned gerontologist, Professor Andrea Maier who brings an invaluable perspective and continues to break new ground in age-related diseases research.

This issue emphasizes the need for standardization in research methodologies to optimize comparability, which in turn may accelerate potential breakthroughs. As always, we strive to bridge the gap between the scientific community and policy makers, underscoring the urgent necessity for gerontology insights to inform public health strategies, legislation, and societal views on aging. Stay tuned for a captivating exploration of gerontology with Professor Maier.

VitaDAO Funded Research Projects

Viktor Korolchuk’s project, which aims to discover novel autophagy activators, will be the first VitaDAO project to undergo Synthesis of its IP-NFT after receiving a 100% majority in the tokenholder vote.

Synthesis will create direct capital for the project and incentivise the VitaDAO community to contribute and move it into overdrive.

Longevity Literature Hot Picks

Preprint Corner

VitaDAO’s very own longevity overlay journal - The Longevist - had its first on-chain vote to determine what our team of curators think are the most exciting preprints of Q1 2023. We are aiming to launch the website later this month.

Prizes will be awarded for nominating preprints which make it into future issues of The Longevist. If you would like to nominate a preprint for inclusion in Q2 2023, then please follow this link - deadline 30th June 2023.

This month we are featuring 6 new preprints which are all available to review on our reviewing platform The Longevity Decentralised Review (TLDR) in return for a bounty of 50 $VITA each. Simply follow the above link to the TLDR page and get reviewing! What's more, we will be continuing the 50 $VITA bounty for reviewing any of the preprints featured in previous issues of this newsletter.

DNA repair and anti-cancer mechanisms in the longest-living mammal: the bowhead whale

Initiation phase cellular reprogramming ameliorates DNA damage in the ERCC1 mouse model of premature aging

Cellular Senescence is a Double-Edged Sword in Regulating Aged Immune Responses to Influenza

DNA methylation rates scale with maximum lifespan across mammals

Breast cancer risk based on a deep learning predictor of senescent cells in normal tissue

Causal evidence that herpes zoster vaccination prevents a proportion of dementia cases

Published Research Papers

DNA methylation clocks for clawed frogs reveal evolutionary conservation of epigenetic aging

DNA methylation-based aging is conserved in frogs and mammals. The identified age-related CpGs are located in neural-developmental genes, implying a connection between epigenetic aging and age-associated diseases. The study opens avenues for using frogs as an aging model.

Senotherapeutic peptide treatment reduces biological age and senescence burden in human skin models

Researchers identified a peptide called Pep 14 that can effectively reduce senescence burden in human skin cells without toxicity. By modulating the activity of a specific enzyme involved in DNA repair and senescence pathways, Pep 14 improved the skin phenotype and reduced the biological age of aged skin samples in a safe manner.

Distinct longevity mechanisms across and within species and their association with aging

Study across 41 mammalian species reveals genetic signatures of lifespan control, including shared mechanisms like downregulated Igf1 and upregulated mitochondrial genes. Lifespan-extending interventions target genes related to energy metabolism.

Exercise reprograms the inflammatory landscape of multiple stem cell compartments during mammalian aging

Exercise rejuvenates aging stem cells, improves tissue regeneration, and reduces inflammation. This study examines the molecular changes induced by exercise in various stem cell compartments, highlighting its positive effects on intercellular communication and immune cells.

Effects of hunger on neuronal histone modifications slow aging in Drosophila

The sensation of hunger, by limiting BCAAs or directly activating hunger neurons, extends lifespan in Drosophila. Hunger-induced changes in neuronal histone acetylome seem to play a role.

Multivitamin Supplementation Improves Memory in Older Adults: A Randomized Clinical Trial

Participants taking multivitamins had better immediate recall memory compared to those taking a placebo. This effect was sustained over a three-year period, suggesting multivitamin supplementation could be a safe way to maintain cognitive health with age.

Leukocyte telomere length (LTL) is associated with various health outcomes. Longer LTL is linked to increased neoplasm risk, while shorter LTL is associated with conditions like coronary heart disease and rheumatoid arthritis.

Autophagy enables microglia to engage amyloid plaques and prevents microglial senescence

Activated autophagy in disease-associated microglia helps maintain amyloid plaque homeostasis and prevent senescence. Inhibiting microglial autophagy worsens neuropathology, while removing senescent microglia could be a therapeutic strategy for AD.

Discovering small-molecule senolytics with deep neural networks

Deep learning was used to identify three drug-like compounds that selectively target senescent cells, similar to a known senolytic drug. These compounds reduced senescent cell burden in aged mice, highlighting the promise of deep learning in drug discovery.

Lifelong exercise training promotes the remodelling of the immune system and prostate signalome in a rat model of prostate carcinogenesis

Lifelong exercise training in a rat model of prostate cancer led to increased γδ T cells and lymphocyte infiltration in the prostate tissue. Exercise also induced changes in the expression of Oestrogen Receptor and Mitogen-activated Protein Kinase 13.

Region-based epigenetic clock design improves RRBS-based age prediction

Epigenetic clocks for mouse RRBS data have poor performance on external datasets. A study introduces regional blood clocks (RegBCs) that improve age prediction by using average methylation over large regions and outperform individual CpG-based techniques.

Thrombomodulin (THBD) signaling identified as a key pathway in senescence. Inhibiting THBD signaling with vorapaxar eliminates senescent cells and restores tissue homeostasis in liver fibrosis models.

Alpha‑ketoglutarate supplementation and BiologicaL agE in middle‑aged adults (ABLE)—intervention study protocol

The ABLE trial investigates the effects of Alpha-Ketoglutarate (AKG) on aging in humans. Participants will receive AKG or a placebo for 6 months, with follow-up for 3 months. The study aims to measure changes in DNA methylation age, inflammatory and metabolic parameters, strength, arterial stiffness, skin autofluorescence, and aerobic capacity.

Published Literature Reviews

Chronic kidney disease promotes ageing in a multiorgan disease network

Chronic kidney disease has been identified as a significant risk factor for accelerated aging in multiple organ systems. This highlights the interconnectedness of age-related chronic diseases and their impact on mortality.

Senescent Cells: A Therapeutic Target in Cardiovascular Diseases

This review emphasizes the impact of senescent cells on different cardiovascular cell types and discusses the potential of senotherapeutics for treating cardiovascular diseases.

Senescence: a double-edged sword in beta-cell health and failure?

In pancreatic beta-cells, senescence contributes to age-related decline and diabetes. Targeting senescence is a promising approach for diabetes treatment. This perspective discusses the importance of senescence in beta-cell homeostasis and pathology.

Job board

Looking for a job in longevity research? Check out jobrxiv - we have saved you milliseconds by entering “aging” in the keyword search, but enjoy searching for whatever your research interests are!

Wyss-Coray Lab looking for a research assistant/associate to work on microglia, HSCs, lipidome or aging clocks

Hansen lab at the Buck are looking for new postdocs!

The focus of the research is to understand how the basic cellular recycling process called autophagy is regulated during aging, using the nematode C. elegans and mammalian cell culture systems, and a combination of biochemical, imaging, and genetic approaches.

The Benayoun lab at the Leonard Davis School of Gerontology at the USC is seeking a Research Lab Technician. They aim to use mice to understand sex differences in the aging process!

News

Hevolution Foundation Geroscience Research Opportunities (HF-GRO) Awards Unveiled, with a Budget of up to $115M Over Five Years

Resources

Longevity Biotech Landscape

Ada Nguyen provides us with an overview of the longevity biotech landscape, by sorting the different companies into 4 key therapeutic areas: reset & repair, replace, reprogram and discover.

Prizes

The Maximon Longevity Prize for Translational Research

Awards outstanding breakthrough research in the field of longevity that can be translated for clinical or non-clinical applications and has the potential to substantially increase health span or life span of humans.

They are welcoming applications from all academic/non-profit researchers, inventors, scientists, students or startup founders who either published breakthrough research, hold the patent or are in very advanced stages of research.

Articles

Biopharma Targets the Untapped Potential of the Human Healthspan

The Longevity Skeptic

The Secrets of Aging Are Hidden in Your Ovaries

Can a Kidney Transplant Drug Keep You From Aging?

Inside the Secretive Life-Extension Clinic

Speaking of Illusions: Sirtuins and Longevity

Combilytics: Taking a combined approach to senescence

NPR-8: The Protein That Could Extend Human Lifespan in a Warming World

The unexpected force that may make us get less sleep

More geriatricians needed to meet the needs of the UK’s ageing population

Why do some people live to be a 100? Intestinal bacteria may hold the answer

Vitalik Buterin Exclusive Interview: Longevity, AI and More

Speaking of Vitalik, he published a longevity pyramid short survey on his website. See where your health philosophy fits in!

Conferences, Workshops and Webinars

Meet the most inspiring speakers and experts gathering to discuss their present research.

Authophagy UK

19-20th June, University of Birmingham, UK

DGfA (German Society for Research on Aging) Annual Meeting

29-30th June, Volkshaus Jena, Germany

5th World Aging And Rejuvenation Conference

17-18 July, Frankfurt, Germany

10-11th August, New York

International Longevity Summit Africa

23-24th August, Johannesburg, South Africa

10th Annual

ARDD

28th August - 1st September, Copenhagen, Denmark

BSRA Annual Scientific Meeting

6–8th September, University of Westminster, UK

The Groningen-Jena Aging Meeting "G-JAM" 2023

28-30th September, European Research Institute for the Biology of Ageing (ERIBA) in Groningen, the Netherlands

Tweet of the Month

By

Matt Fuchs - an excerpt from a twitter thread on the article mentioned above “The Longevity Skeptic”:

Messiness is Good. You want to find and follow scientists who’ve published research over the years that does *not* tell a clean story. “Our goal is to disprove our models,” @mkaeberlein said. Their findings and views should zig and zag as their careers – and science – progress

Follow scientists who write and talk publicly about new evidence that’s convinced them to reevaluate their own positions. Who embrace the inherent messiness of science – that’s the hallmark of an honest researcher

Podcasts and Videos

Pathways to Impact

A series of 12 virtual panels with longevity leaders

Coming on June 21st: Oprah and Dr. Peter Attia Get Real About Living Better for Longer

The Art of Aging: A Tail of Canines, Rapamycin, and Longevity with Dr. Matt Kaeberlein

The Sheekey Science Show: Is aging adaptive?

Interview with Prof. Andrea Maier

Andrea Maier, a renowned professor of gerontology, serves as the Co-Director of the Centre for Healthy Longevity at the National University of Singapore. With over 350 published articles, her groundbreaking research in ageing and age-related diseases is globally recognized, influencing health policy discussions including at the WHO.

What inspired you to enter longevity research?

It was a long, long time ago when I first observed that people age differently. This observation was especially apparent in some older women who exuded an undeniable power and vitality. This led me to question, how does this happen?

At the time, I was already engaged in research within the field of pulmonology, focusing on diseases like cytomegalovirus and other viruses. However, my observations compelled me to switch my focus. First, I transitioned into geriatrics, but I was always drawn towards research into longevity.

I find it truly astonishing how some individuals possess such vitality, even at an advanced age. Admittedly, I was also drawn to this field because it was not overly crowded. For instance, many researchers are interested in diabetes, making it a highly competitive field. Aging and longevity research, on the other hand, is a bit different. I would argue that this is still one of the least explored fields, especially when you consider it through the lens of a physician.

How has the field changed since you started?

In my view, the field hasn't changed at all in terms of the key players. That's something we might need to reflect on. However, the field itself is undeniably evolving. There's been a shift from purely academic pursuits to a greater involvement of startups. Venture capitalists are now engaging in our field and there's also a different level of government inclusion.

In the past, societal discussions were often centered around issues in nursing homes and frailty in hospitals. But now, we're talking about prevention and biological age. We're now in dialogues with organizations like the WHO how to introduce healthy aging to all citizens and the FDA about approving new drugs targeting ageing. This represents a substantial shift from being a purely academic field to one with a much broader scope and a greater societal impact. There should also be ubiquitous presence of regulators to ensure a balanced evolution of the sector.

Speaking of regulators, Singapore is allocating resources and effort to several exciting initiatives aimed at promoting healthy aging and the longevity industry. Could you give us with the latest and most significant updates?

Absolutely, Singapore is at the forefront of implementing many innovative healthcare strategies, largely out of necessity. Singapore boasts one of the highest life expectancies on earth, a distinction it shares with Japan and Switzerland. The country also has a remarkably low fertility rate, and individuals there tend to develop their first diseases at a relatively young age. These factors create a pressing need to lower healthcare costs, increase productivity, and reduce absenteeism. We are focused on stimulating human potential, given the limited natural resources due to the country's small size.

Our current projects, such as the Healthier SG initiative, emphasize preventative actions and cost-benefit analysis, pushing towards a preventative approach in healthcare. They've also established health districts in collaboration with universities, the Housing Board, and industry partners, aiming to study and implement ways to enhance health and longevity.

In addition, Singapore is attracting startups for diagnostic or intervention purposes, utilizing a strong network of researchers and a robust engineering department. At the Center for Healthy Longevity, which I lead, we're conducting clinical research to bridge the gap from preclinical findings to clinical practice, integrating these into the healthcare system through evidence-based longevity clinics. All these efforts are driven by the necessity to enhance human potential.

Which of the current theories of ageing do you think are the most convincing?

There are many theories regarding aging. One such theory I came across is the grandmother hypothesis. This theory posits a question: why do women live beyond their reproductive age? Some research, including studies conducted in Ghana, suggests that there's not much evolutionary need for women to live beyond their reproductive years.

However, I think aging is much more complex. We recently published a paper in Nature Medicine that I'm quite proud of. It demonstrates how different organs within our bodies age at varying rates, and that there's a chain of action. If one organ begins to deteriorate, it's likely that another will soon follow, and we can now predict this.

There's not a singular mechanism behind aging. Rather, I think we're still uncovering the intricate complexities of the aging process and the networks between all the various hallmarks or mechanisms that influence each other.

Certainly, the accumulation of damage over time is a part of aging. But the question is how this damage occurs and how it can be repaired. We are dedicated to developing diagnostics to identify the weakest links in our bodies - which organ needs attention, what the common mechanisms are, and what the organ-specific mechanisms might be.

Other than your own, what do you think have been the biggest/important discoveries in the field?

There have been many significant findings in the field of aging, including the study of senescent cells. Therapies targeting these cells seemed to extend lifespan and improve health span in mice, creating significant excitement.

However, our field progresses through a series of small, yet important steps rather than a single breakthrough. One crucial development is our evolving understanding of the pathophysiology of aging, which has led us to develop diagnostics for biological age. This has the potential to be greatly impactful in our field.

The integration of our knowledge into practical applications that could impact everyday life is particularly exciting. Future interventions, backed by advancements in multi-organ treatments, could significantly increase health span, possibly more than lifestyle changes alone.

Which aspect of longevity research do you think requires more attention?

Currently, our focus is on human research, specifically on different organs' biological ages and how interventions can impact them. Over the last year and a half, we've developed a framework for diagnosing different physiological systems in the human body. If we want to tackle aging effectively, we should be able to measure the impact of interventions on every organ.

We use the eleven physiological systems defined by the Society of Physiology, such as the cardiovascular and endocrine systems. We've found that many trials only use a limited range of outcome parameters such as blood pressure, walking speed, and a few blood parameters. However, we often overlook critical aspects like lung function, women's health, cognitive function and oral health, which could be crucial in aging. Similarly, while many are focused on the microbiome, few are investigating the interaction of several organ systems.

In essence, we are trying to identify and fill the gaps in our understanding of aging across the various physiological systems. By systematically reviewing the literature, we're discovering blind spots and working to address them, to truly comprehend the complexity of aging across our body's many intricate systems.

What mistakes do you think the longevity field has made?

I wouldn't say mistakes. Instead, I'd liken our current stage to that of a toddler. Like a toddler, we are learning, experimenting, observing our environment, and trying different approaches. We're not yet in the stage of 'puberty'; we're still trying to grasp the basic concepts and parameters of our field.

However, one thing we could improve upon is leveraging insights from various specialties and fields. We should learn from others, review the literature, understand different trial designs and methodologies, and apply them in our field. This sort of cross-pollination is essential for growth and advancement.

While it's difficult to pinpoint any specific mistake with a significant negative impact, we must realize that, like a growing child, we will eventually need to mature and refine our approaches. The understanding and patience granted by governments and institutions due to our field's relative youth won't last forever. We need to keep learning and advancing to fulfill the potential of our field.

Is ageing a disease?

Yes! Yes, it absolutely is a disease. And we all have it!

Referring to aging as a disease might be counterproductive when communicating with the general public. However, as a physician, you require a clear diagnosis and treatment plan for your patients.

By treating the underlying mechanisms and consequences of aging, we aim to optimize the overall health and well-being of your patients. Diagnosing aging-related deterioration and assessing biological age allows you to tailor interventions and treatments accordingly. It provides a framework for addressing the physiological and pathological changes associated with aging.

In the medical field, having a clear understanding of aging and its impact on health is crucial for establishing effective practices and offering appropriate interventions to enhance patients' quality of life.

Your lab is mostly focused on longevity interventions in humans. What are the most important endpoints, biomarkers and measurements you look at?
In terms of endpoints and biomarkers, there is a both short-term and long-term answer. I have gained experience from various fields, including endocrinology and oncology, where trial designs have been well-established over several decades. We are now realizing the importance of implementing proper trial designs in the field of aging research as well. Simply relying on observational studies is no longer sufficient for determining outcomes.

Currently, we utilize surrogate markers or parameters, such as C-reactive protein (CRP), which is an inflammation marker. In some of my studies, I use CRP as a primary outcome, not necessarily as a longevity marker, but as an indicator of reduced inflammation. By demonstrating a decrease in CRP levels, we can refer to existing literature to understand the implications of such a change, such as the decreased likelihood of developing cardiovascular disease, for example. Additionally, we employ epigenetic clocks using methylation data in our trials. Instead of relying on a single clock, we use the median of multiple clocks since it is still uncertain which one is the most accurate. This approach allows for risk spreading, which is crucial since our trials have relatively short durations of two to three years. We need to consider outcomes that we would like to avoid in the long run, even if they might take a hundred years to manifest.

However, it is important to note that the long-term outcome parameters are more organ-specific and highly significant. In my research, the population I focus on for randomized control trials is much younger, typically between 30 and 60 years old. Therefore, using these specific endpoints would require significantly longer follow-up periods. It is also worth mentioning that I'm not primarily interested in dichotomous outcomes where individuals either develop a disease or not. Instead, I focus on continuous outcome parameters indicating the function of organs.

Ultimately, the decline of function in aging is a continuous process, and our goal is to determine how much decline we can prevent to make a clinically relevant impact. Currently, our field is in the process of understanding what is considered clinically relevant and within what timeframe such interventions need to take place.

As standardization can be a concern in human aging studies, can you elaborate on your ability to compare your findings with other similar studies conducted by various institutions, including academic and clinical ones?

This is a huge problem! It is a big mess at the moment and this brings me back to the toddler analogy. We haven't defined or standardized our approaches yet. I often find it challenging to conduct meta-analyses in systematic reviews due to the heterogeneity of studies. This serves as an alarm signal that standardization is necessary.

That's why I founded the Healthy Longevity Medicine Society (HLMS) to bring together healthcare professionals, scientists, and entrepreneurs. One of our major goals in HMS is to establish standards in research. This includes standardizing how we measure parameters like musculoskeletal or women’s health outcomes. Currently, there are numerous different ways to measure these parameters, leading to inconsistent outcomes.

We have learned from other fields, such as cardiology, that standardization is crucial. For example, we know how to measure blood pressure accurately by ensuring individuals rest for 3 to 5 minutes in a quiet room. We are now at the stage where we need to standardize our methods, what we measure, and when we measure it.

To address this issue, we established a consortium of publicly funded hospitals that are setting up longevity clinics. We are currently designing standardized protocols for measuring physiological systems in humans. By adhering to these protocols, we can ensure consistency. The next step will be certification, where practitioners receive a certificate for following the standardized protocols.

We need to accelerate the implementation and scalability of these standards to effectively reverse the aging process. Without standardization, we are just surrounded by noise caused by inconsistent methodologies.

When selecting interventions to test in humans, how much significance do you place on data derived from animal models, and what has been the level of translatability in your experience?

I always look at animal models as an initial step before starting a study. We conduct systematic reviews and analyse animal and human studies to inform our translational approach. Learning from past experiences, we have seen successful translation in the longevity field. For example, supplements that have shown positive effects in animal models often have a good success rate when translated to humans. The success depends on the mechanism being studied, as certain mechanisms are conserved across species.

However, it's important to note that we don't solely rely on animal data. If a therapeutic intervention shows safety in humans, and the animal data is not available or necessary for safety assessment, we may proceed directly to human trials. The primary consideration here is the safety aspect. Once we establish the safety, we can implement it in human studies to assess the effects.

Outro

Thank you for staying with us until the very end and as always we encourage you to reach out to us about content you’d like us to discuss in our next issues. See you next month!