Introduction
Welcome back Vitalians! Stop the press — the Impetus Longevity grants are back!
Having already deployed 24M USD to fund longevity research, round 3 is now open with 10M USD of funding, so if you have a great idea, get your application in before 31st August!
And the good news doesn’t stop there! VitaDAO has just opened another round of the Longevity Fellowship. We provide need-based micro-grants of up to $2,000 USD to passionate scientists, students, and longevity enthusiasts to delve deeper into their research interests, attend conferences, and join programs such as the Longevity Biotech Fellowship.
Quick tip: funding is distributed on a rolling basis so don’t wait too long to apply!
If real estate agents like to inform you it’s all about “location, location, location”, then drug developers would likely tell you it’s all about “delivery, delivery, delivery”.
It’s simply not enough to have a drug which works in a test tube,
it has to be able to reach the intended target within the organism. The bioavailability of a drug can be diminished by various obstacles, from having to pass through the GI tract or the blood-brain-barrier, to navigating solid tumour microenvironments. As such, scientists are constantly looking for new ways to improve drug delivery, such as innovative nanotechnology-based carriers or developing prodrugs which can convert to being pharmacologically active at the site they are required. This month we’re excited to bring you an interview with Matthew Yousefzadeh, who has made significant contributions to the aging field, and touches on the bioavailability hurdles associated with the promising senolytic drug fisetin — enjoy!
Longevity Literature Hot Picks
Preprint Corner
The votes are in — The Longevist curators have decided what they think are the most important preprints of Q2. Before we publish the Q2 Issue of the Longevist, take a look at the inaugural issue of The Longevist which is now live!
Check out our first batch of preprints of Q3
with these July submissions. These will each be entered into the Q3 longlist to be in the running to receive a coveted place in The Longevist. They are also available to review on our reviewing platform The Longevity Decentralized Review (TLDR) for a bounty of 50 VITA per review.
As always, you can refer preprints to The Longevist and receive a bounty of 50 VITA for each one that makes the editors’ shortlist or 200 VITA if it makes the curators’ top 3.
LEF1 isoforms regulate cellular senescence and aging
Preserved striatal innervation and motor function despite severe loss of nigral dopamine neurons following mitochondrial dysfunction induced by mtDNA mutations
Alterations of the gut microbiome are associated with epigenetic age acceleration and physical fitness
Amyloid β accelerates age-related proteome-wide protein insolubility
The principal component-based clinical aging clock (PCAge) identifies signatures of healthy aging and provides normative targets for clinical intervention
Systems Age: A single blood methylation test to quantify aging heterogeneity across 11 physiological systems
Machine Learning identifies conserved traits that influence lifespan and healthspan responses to dietary restriction
β-hydroxybutyrate is a metabolic regulator of proteostasis in the aged and Alzheimer disease brain
Somatic mutations in human ageing: New insights from DNA sequencing and inherited mutations
A comprehensive atlas of the aging vertebrate brain reveals signatures of progressive proteostasis dysfunction
Glial-derived mitochondrial signals impact neuronal proteostasis and aging
Published Research Papers
Chemically induced reprogramming to reverse cellular aging
The Sinclair lab have identified chemical cocktails which can reverse transcriptomic age in cells. Thus they claim that age reversal can be achieved by chemical means. This paper has sparked controversy due to the speed of publication, questions of novelty, and overhyped claims. Take a read and make up your own mind!
The million-molecule challenge: a moonshot project to rapidly advance longevity intervention discovery
From microscopes to space telescopes,
technology and science need to work together to make advances possible. Using the WormBot-AI automated data capture and analysis technology, the Kaeberlein lab are taking on the ambitious challenge of screening a million molecules for their effects on lifespan in C. elegans.
Large-scale across species transcriptomic analysis identifies genetic selection signatures associated with longevity in mammals
Among mammals alone, lifespan can vary over 100 times between species. Here the authors performed transcriptomics across numerous species and identified that translation fidelity pathways correlate with lifespan and methionine restriction genes are under strong selection in long-lived mammals.
Here we have back to back published studies showing that senescent macrophages drive lung cancer and accumulate in aging
- Clearance of senescent macrophages ameliorates tumorigenesis in KRAS-driven lung cancer
- Senescent alveolar macrophages promote early-stage lung tumorigenesis
More than bad luck: Cancer and aging are linked to replication-driven changes to the epigenome
The Levine lab’s study suggests that aging and cancer share a common epigenetic replication signature, termed CellDRIFT. This signature increased with age across tissues, distinguished tumor from normal tissue, was escalated in normal breast tissue from cancer patients, and could be reset upon reprogramming.
Multi-omic rejuvenation and life span extension on exposure to youthful circulation
Heterochronic parabiosis (HPB) in mice has shown significant rejuvenation effects, improving physiological parameters and extending lifespan. HPB reduced the epigenetic age of blood and liver, with the effect persisting even after detachment. The transcriptomic and epigenomic profiles suggest a global rejuvenation effect.
Maternal aging increases offspring adult body size via transmission of donut-shaped mitochondria
Maternal age significantly influences offspring adult traits like body size. This study utilized C. elegans to explore the mechanisms, revealing aged mitochondria transmitted from older worms are rejuvenated in offspring in an AMPK-dependent manner. This early-life mitochondrial dysfunction triggers AMPK and TGFβ signaling, increasing adult offspring size.
Multiparametric senescent cell phenotyping reveals targets of senolytic therapy in the aged murine skeleton
Using mass cytometry, researchers identified and analyzed senescent cells in aged mice at single-cell resolution. They found these cells in certain skeletal cell populations could be robustly cleared by senolytic therapies, providing a method to target senescent cells in vivo.
Lifespan-extending interventions induce consistent patterns of fatty acid oxidation in mouse livers
A study investigating the gradual molecular dysregulation in aging finds that lifespan-extending interventions like acarbose, 17α-estradiol, rapamycin, and calorie restriction generally tighten the regulation of biological modules. These patterns are similar across interventions, particularly in processes such as fatty acid oxidation, immune response, and stress response.
Pan-primate studies of age and sex
Horvath presents accurate pan-primate epigenetic clocks based on DNA methylation profiles from 2400 tissues across 37 primate species. The study explores the impact of age and sex on cytosine methylation, identifying 11 sex-related CpGs on autosomes. The findings provide insights into conserved age- and sex-related epigenetic changes and biomarkers of aging in primates.
Predicting lifespan-extending chemical compounds for C. elegans with machine learning and biologically interpretable features
Researchers used machine learning to analyze DrugAge, a database of compounds that modulate lifespan in model organisms. They identified the importance of the “Glutathione metabolic process” and predicted new promising compounds for extending lifespan, including nitroprusside, an antihypertensive medication.
Published Literature Reviews
Chronic inflammation and the hallmarks of aging
The review suggests that chronic inflammation, known as “inflammaging,” is a critical driver of aging and age-related diseases. It is linked with other aging hallmarks, exacerbating cellular dysfunction and advancing aging. Targeting inflammation could be key in developing anti-aging interventions and addressing age-related conditions.
An updated landscape of cellular senescence heterogeneity: Mechanisms, technologies and senotherapies
The review emphasizes the critical role of senescent cells in aging, and the need for better identification methods. Despite the challenge posed by the heterogeneity of senescence, high-throughput technologies like single-cell RNA sequencing could enable improved analysis and potential discovery of new markers.
Stress, diet, exercise: Common environmental factors and their impact on epigenetic age
This review explores how lifestyle factors influence the DNA methylation landscape, as revealed by epigenetic aging clocks. Lifestyle factors can impact DNA methylation and consequently influence biological aging. Understanding these relationships could provide valuable insights for people interested in creating a lifestyle designed to promote longevity.
Spatial mapping of cellular senescence: emerging challenges and opportunities
This review discusses the challenges of mapping senescent cells, crucial for understanding aging. Current single-cell technologies lack spatial data, which is key due to the interactive nature of these cells. New spatial imaging methods are needed to create a comprehensive senescent cell atlas.
Job board
VitaDAO’s portfolio company BE therapeutics is looking for a scientist with tissue engineering or neuro lab experience for some exciting work on brain replacement lead by Jean Hebert. Send CV to jean.hebert@einsteinmed.edu to be considered.
Korolchuk lab
in Newcastle University are hiring for an exciting new position of lab technician which will support an industrial project in collaboration with Procter & Gamble.
Explore new mechanisms of how DNA damage drives aging and alters heritable genomes at the Schumacher Lab at CECAD Cologne. They are seeking enthusiastic postdoc candidates with a background in genetics, cell biology, biochemistry or computational biology.
Prof. Marco Demaria
is looking for an enthusiastic and ambitious PhD candidate to join the Laboratory of Cellular senescence and age-related pathologies (Groningen, Netherlands), to work on a project studying the contribution of senescent cells to inflammatory and fibrotic chronic disease.
Research Associate position available
in Dr. Gordon Lithgow’s laboratory at the Buck Institute for Research on Aging. The Lithgow lab combines biochemical, molecular, and genetic techniques to address fundamental questions about aging in C. elegans.
Brieno-Enriquez lab
is looking for two motivated postdocs to explore reproductive aging in the naked mole rat. They will leverage the NMR to explore mechanisms that rejuvenate the ovary and extend both reproductive lifespan and overall health.
News and Media
FDA grants full approval to Leqembi, opening up coverage of Alzheimer’s drug by Medicare
After a dispute with the publisher resulted in the resignation of 5 editors-in-chief from Aging Cell — the former editors have now returned with a new scientist-led journal — Aging Biology — which is now accepting submissions and publishing papers.
Check out Lada Nuzhna’s reflections on 2 years of going after risky aging science.
USA Today: Want to live healthier longer? Scientists aim to improve life quality over quantity
8 healthy habits that may add 24 years to your lifespan
The Wall Street Journal: The Longevity Clinic Will See You Now — for $100,000
Twenty minutes of daily exercise can help reverse frailty and build resilience in over 65-year-olds
The boom of the anti-aging market: How to get people to live to be 120 (and in good health)
The Daily Mail catches up on the drama in the aging research world: EXCLUSIVE: Harvard claims it found the elixir of youth — but experts call it ‘hype’
Mitochondrial DNA fragments in blood shown to be important biomarkers for aging
Peter Fedichev Explains His Theory of Aging
Healthy longevity is not only for the neurotypical
Resources
Norn Group’s
age related diseases overview: an excellent resource of early stage startups in the longevity space that are looking for an initial clinical indication to target
Prizes
Rewarding the most impactful research in longevity
Substantially increasing the human lifespan. The Amaranth Prize gives no-strings attached funding to the best research in Longevity.
Conferences
10–11 August, NY, USA and virtual
17–20 August, Dublin Ireland
Aging Research & Drug Discovery (ARDD)
28 August — 1 September, Copenhagen, Denmark
British Society for Research on Aging Annual Scientific Meeting (BSRA ASM)
6–8 September, London, UK
7–9 September, LA, CA, USA
Expo and Convention: Independent Ageing 2023
13–15 October, Aichi, Japan
7–8 November, Buck Institute for Research on Ageing, Novato, CA, USA
Tweet of the Month
Adam Gries (@adamgries):
The idea that we shouldn’t work hard to extend lifespans (which has been echo’ed by @ elonmusk) would make more sense , if we weren’t *already* spending like crazy to increase lifespans, just doing it poorly.
Trillions now go to the last 5 years of life. […]
Podcasts and Webinars
Join us for a Twitter live discussion on the latest epigenetic clock research
7 August, virtual
Norn Group presents: Near Future Skill Gaps in Software & ML discussing current & impending changes impacting aging bio research due to advances in software & ML. Featuring Joe Betts-LaCroix, Luca Naef, Andy Lee, and Sam Spurlin
9 August, virtual
Did you miss our Robust Mouse Rejuvenation Twitter live with Aubrey de Gray, Caitlin Lewis,
Kelsey Moody, & Danique Wortel? Don’t worry, the recording is up.
We also interviewed Sergey Young!
NUS Medicine’s Healthy Longevity Webinar Series
This month:
Ovarian Ageing: A Target for Geroprotection in Women | Prof Suh Yousin
AI and robotics | Dr Alex Zhavoronkov
Taurine deficiency as a driver of ageing | Asst Prof Vijay Yadav
Funding Opportunities
Research: Impetus Longevity grants
Micro-grants: VitaDAO Longevity Fellowship
Interview with Matthew Yousefzadeh
Matthew is an instructor at Columbia University Medical Center where he works on mechanisms of aging, in particular how DNA damage and cellular senescence contribute to cell autonomous and non-autonomous aging.
What inspired you to enter longevity research?
Previously, my background was in cancer biology and much of my PhD work was on how specialized DNA polymerases could play protective roles in limiting genotoxic stress, but their levels had to be tightly regulated. Too much of these enzymes could be permissive to tumorigenesis or make them refractory to treatment. I got into cancer biology because during my freshman year of college my grandmother survived one bout with breast cancer but succumbed to a second round of cancer. Likewise, as I was finishing my PhD, I saw my mom start to accumulate some age-related health issues and she died at a young age. This was the impetus for me to get interested in aging research. Going to Laura Niedernhofer’s lab was a no-brainer and provided a natural transition for me where I could take my DNA repair background and use it to study senescence.
How has the field changed since you started?
My plan was to go to Laura’s lab to study senescence that was induced by DNA damage or through DNA repair deficiency. At the time, I had no clue what senolytics were and the first senolytics paper was published a few weeks before I showed up to the lab. Obviously, the senescence field has matured a lot since then and still has a way to go. Outside of that there have been incredible discoveries in many of the other pillars of aging like the broadened use of epigenetic clocks, epigenetic reprogramming, and use of companion animals as a method to study aging. The field felt a bit slower back when I started my postdoc, and it is moving much more rapidly now. This is both great because I feel like the speed of progress is picking up, but terrifying from a standpoint of how many good papers are coming out every day that I need to read up on. It is a fantastic problem to have though! Recently in the past few years there seems to be a greater public interest in aging, and I think it has turned into a prime opportunity to bring young enthusiastic minds into the field of geroscience. Also, we are seeing people in other diseases spaces like cancer begin to get much more serious about looking at the interplay between their disease of interest and aging. From a commercial standpoint the number of longevity companies was really limited to Calico and in the realm of senescence, Unity Biotechnology. In the past few years, this aging biotech landscape has exploded, which I find to be a positive sign.
Other than your own, what do you think have been the biggest/important discoveries in the field?
While some of these are controversial spaces, I think the work done by too many labs to individually list on these topics are a boon for geroscience: 1) Levels of in disease and aging, 2) epigenetic reprogramming and functional outcomes in regards to rejuvenation, 3) understanding how centenarians age so well, 4) transgenerational effects on aging and longevity, and 5) the use of C. elegans to conduct high throughput screening of monotherapies and combinations to determine possible geroprotectors. Each of these are very important and in their own individual way could serve as a disruptor in the field of aging.
What advice would you give to people currently working in longevity research?
Find something you care about working on and go all in on it. Some days you will love it and other days it will frustrate the hell out of you. I have seen some really good scientists run away from projects when they get their first piece of negative data or experience some difficulty. Some of them have tried to jump from what they thought was a hot project to next hot project because it was “cooling off” and eventually they burnt themselves out. Learning resiliency can be tough but find something that you can stick and see it through. It is so rewarding! Another piece of advice is to find a place where people are invested in your development. I tell graduate students and other early career researchers to chase mentorship and not projects. Good mentorship can set you on a path to success when you are at such a nascent stage in your career. I also think programs like the MBL Biology of Aging Advanced Research Training Course that was created by Jennifer Garrison and Will Mair will serve as excellent conceptual and technical primers for people new to the field or looking to expand their skillsets. Get involved! Join the American Aging Association or the Gerontological Society of America and get involved with the trainee chapters or other committees. Trainees can take part in the peer review training program at Geroscience where they can independently review manuscripts. If you are interesting, contact me.
Which aspect of longevity research do you think requires more attention?
I’m going to say there are two big areas that deserve more attention: 1) validation of biomarkers and reagents; and bandwidth and best practices for bioinformatic analysis. The first has been a long-standing issue not just for aging but for other fields as well. We all know biology can plagued by poor reagents like antibodies that have not been properly validated or how many of the markers in my own field of senescence are non-specific. Discovering better markers and building better tools that we are confident will go a long way to expediting progress. Let’s face it, resource validation is not sexy, but it is vital.
To the second point, it has been incredible to watch the explosion of ‘omic and multiomic analysis in the field of aging. I wish I had access to single cell RNAsequencing as a first-year postdoc, it would have made my life a lot easier. A lot of us, me included, are trying to play catch up to the ever-shifting landscape of technology in this area and its inherent strengths and weaknesses. We desperately need bioinformatics support to help us process the mountains of data and we have been fortunate to draw a lot of very talented people from the tech sector into aging in the last few years as we also home grow bioinformatics talent. My last point on this topic is that many of us are looking for resources on best practices for these topics so that we can plan and execute the best possible experiment. One example of this is a recent publication from Param Priya Singh and Bérénice Benayoun on “Considerations for reproducible omics in aging research.” I think this manuscript is incredibly informative and can serve as a great reference for anyone using ‘omics to study aging. Speaking of advice, I am also incredibly fortunate that Bérénice is a friend and has been generous with giving me advice as a postdoc and now as a PI.
Is ageing a disease?
This is how you start a fight over beers when you get a bunch of aging researchers together. I think it is a disease, but also a natural and omnipresent condition. A very milquetoast take right? Realistically it probably sits in between the two states. Some people feel very strongly about it, but I’d rather focus on the science rather than semantics.
You have shown that fisetin is a senotherapeutic that extends health and lifespan in mice — what do you think is the biggest challenge in bringing fisetin to the clinic?
Fisetin is interesting in that we wanted to demonstrate that a senolytic could be safe but effective. Dasatinib, a chemotherapeutic that is used in combination with quercetin as a senolytic, has side effects. The natural product fisetin was originally identified through screening other flavonoids to see if they had more potent senotherapeutic effects than quercetin. I think two big hurdles for bringing fisetin to the clinic is that since it is a natural product it has a very limited intellectual property (IP) position and from a drug standpoint it has poor bioavailability. To address the second point, Kyle Brewer, a talented aging biologist, at ETTA Biotechnology is working to develop an optimized formulation to better deliver fisetin. Meanwhile the laboratory of my former co-mentor at the University of Minnesota, Paul Robbins, is developing fisetin analogs to increase potency and bioavailability, as well as create novel IP around these analogs. Paul has co-founded Itasca Therapeutics, a platform company which I currently serve as the CSO for, to develop these compounds and other senolytics. Itasca Therapeutics was created because we found that the typical funding mechanisms for academic research were insufficient to push lead compounds discovered in the academic lab further into the drug development thus the needs to acquire private funding.
Which other senolytic strategies do you think hold promise and what are the potential negative impacts of removing senescent cells?
The field of senolytics is growing and so are their approaches. These include everything from the use of AI-guided drug design, protein degraders of targets (PROTACs), CART cells, and activation of immune clearance mechanisms. I find Anil Bhushan’s work on senescent cell elimination by invariant (i)NKT cells to be both intriguing and refreshing. Many of us are looking at senescent cell accumulation as purely detrimental and studying them in the gain of function context. Others like Anil view senescent cells are serving a regulatory role and asking questions about why we fail to clear them as we age. This work is addressing the other side of the senescence equation (loss of function in the form of immune clearance). Furthermore, not all senescent cells are deleterious and should be cleared. A few years ago, a group showed that genetic clearance of senescent liver sinusoidal endothelial cells (LSECs) that expressed high levels of the p16Ink4a gene had detrimental effects and caused a pro-fibrotic response in the livers of these mice. These cells were not affected when the mice were treated with dasatinib and quercetin. Furthermore, it was found that expression of p16Ink4a specifically in the pancreatic beta cells of transgenic mice enhanced glucose-stimulated insulin production and provided an unexpected benefit to diabetic mice. Studies like these serve as a cautionary tale to not be hasty to eliminate all senescent cells or all cells that express p16Ink4a. We are fortunate that the newly created NIH Common Fund Cellular Senescence Network program is working to better characterize the heterogeneity of senescent cells in multiple tissues of both humans and mice across the lifespan. This could provide greater insight into specific senescent cells and how best to target them.
Which other interventions do you think hold promise for improving human healthspan/lifespan?
One of the most efficient interventions to democratize longevity is exercise as medicine. Beyond that interventions range anywhere from practical to promising to vaporwave. If I had to pick a front runner it would be mTOR inhibition whether it be in the form of rapamycin or newer generation compounds that selectively target mTORC1. It is one of the most reproducible results throughout multiple animal models and the human data on mTOR inhibition has been very encouraging. Columbia University Medical Center, where my lab is located, has just launched the VIBRANT (Validating Benefits of Rapamycin for Reproductive Aging Treatment) study, VIBRANT is being co-led by Yousin Suh, a well-known figure in the field of aging and director of reproductive aging at CUMC. If rapamycin treatment can slow down ovarian aging in humans, that would be huge!
You have also shown that an aged immune system has a causal role in driving systemic ageing — which therapeutic strategies do you think could help tackle this?
Speaking of mTOR inhibition, Joan Mannick’s work on vaccination rates in the elderly and outcomes with respiratory tract infections or Tyler Curiel’s work on cancer models was very inspiring to my own work. Beyond that the work on enhancing senescent cell clearance via immunotherapy is very exciting. Overall, I think it is going to take a combinatorial approach to rescue some of the age-related deficits in immune function.
You recently relocated to Columbia University Medical Center — what can we expect from the Yousefzadeh lab?
I am really interested to continue studying the role of senescent immune cells and how they affect systemic aging through interorgan communication. Beyond that I am interested in the role of cellular senescence (immune cells and beyond) on adverse outcomes in pathogenic infections. Previously, I established a human senescence core at UMN and plan to do the same at CUMC to help measure biomarkers of aging in humans. Moving to New York City has put me in close contact with long-time collaborators like Derek Huffman at Albert Einstein College of Medicine and allows me to foster new collaborations. Beyond that I have a strong interest in DEIB and have participated in multiple outreach programs that work to provide opportunity and exposure to promising young scientists from all backgrounds. I want to continue my work with these programs and help mentor the next generation of scientists that want to embark on careers in aging and longevity. If you are in NYC, let’s grab a slice of pizza and talk science. My treat!
Outro
We appreciate you sticking with our research newsletter for another month and hope the content we curate is useful!
This time we leave you with a short summary video of what VitaDAO does and why.
