Introduction
Welcome back, Vitalians! Please join us in congratulating the ARTAN team for raising $300k in VitaDAO’s 2nd IPT launch! We look forward to bringing you more updates on this exciting project as the team works towards developing therapeutic candidates aimed at suppressing mutations that drive aging.
If you recall, last year there was quite a stir in the longevity community when funding for the Dog Aging Project was discontinued. Now, you have the opportunity to support this great initiative by contributing to help continue the study.
In other news, Alpha Fold has achieved another milestone with the release of AlphaFold 3, which now predicts the structure and interactions of all of life’s molecules!
This month, we're excited to bring you an interview with Dr. Adam Freund, CEO of Arda Therapeutics - a biotechnology company taking aim at chronic diseases and aging by eliminating the pathogenic cells that drive these conditions. Dr. Freund shares his insights from his extensive experience in longevity research, which spans academia, industry, and founding his own company. Enjoy!
Longevity Literature Hot Picks
Preprint Corner in collaboration with
The Longevist is a preprint overlay journal spotlighting the most promising longevity studies each quarter.
Check out these latest preprints, which have all been entered into the 2Q24 longlist to be in the running to receive a coveted place in The Longevist. As always, you can refer preprints for consideration in The Longevist and the person who recommends the highest-voted preprint of the quarter will receive a prize of 200 VITA!
IF1 Protein Controls Aging Rate
This paper reveals that inhibiting F1F0 ATP hydrolysis, while allowing ATP synthesis, correlates with increased maximal lifespan and reduced aging biomarkers in mice, suggests metabolic heat generation via F1F0 ATP hydrolysis is vital for homeothermy, and proposes a novel class of anticancer drugs that selectively inhibit F1F0 ATP hydrolysis, potentially slowing aging and sparing normal cells from harmful side effects.
In vitro heterochronic parabiosis identifies pigment epithelium-derived factor as a systemic mediator of rejuvenation by young blood
This study establishes an in vitro heterochronic parabiosis system to identify factors like pigment epithelium-derived factor (PEDF), which extends replicative lifespan of human fibroblasts, reverses age-related decline in aged mice, and supports PEDF as a key mediator of the rejuvenating effects of young blood, offering a valuable platform for discovering circulating factors involved in aging and rejuvenation.
In vivo reprogramming of Caenorhabditis elegans leads to heterogeneous effects on lifespan
This study demonstrates for the first time that inducing in vivo reprogramming in C. elegans using a heat-inducible system can lead to premature death with varying toxicity across developmental stages, paralleling the effects observed in mice, and suggests this model could enhance our understanding of development and in vivo reprogramming.
The CALERIE™ Genomic Data Resource
The CALERIE-2™ trial, the first randomized controlled study of long-term caloric restriction (CR) in healthy, non-obese humans, supports CR's benefits on biological aging, and its resultant publicly accessible genomic datasets from multiple tissues provide a valuable resource for advancing translational geroscience.
The Latent Aging of Cells
The authors hypothesize that DNA methylation, beyond being an informative biomarker, could be crucial to understanding the interplay between aging, (de)differentiation, and epigenetic reprogramming, as our unsupervised analysis reveals shared methylation patterns across these processes and a distinct aging signal in tissues that resists reprogramming, suggesting that aging and reprogramming are not fully mirrored processes.
Pleiotropy and Disease Interactors: The Dual Nature of Genes Linking Ageing and Ageing-related Diseases
Ageing-related diseases (ARDs), despite their diverse phenotypes, share common biological processes rooted in ageing mechanisms, which can be explored for unified therapeutic strategies; using a network approach, we found that ageing-related genes are indirectly associated with multiple ARDs via protein-protein interactions and KEGG pathways, with genes affecting multiple ARDs either being broadly modulatory or specialized, and machine learning identified potential novel ageing-related genes involved in protein metabolism, stabilization, development, and cellular response to stimuli.
Published Research Papers
Aging clocks based on accumulating stochastic variation
Featured in the inaugural edition of The Longevist - this innovative research shows that aging clocks can be built on accumulating stochastic variation.
Temporal dynamics of the multi-omic response to endurance exercise training
The Molecular Transducers of Physical Activity Consortium detailed extensive molecular changes in rats undergoing endurance training, identifying key pathways affecting health-related conditions. Their comprehensive data is publicly available for further exploration of exercise's effects on multiple tissues.
Brain-muscle communication prevents muscle aging by maintaining daily physiology
Studies on arrhythmic mice demonstrate that linking central and muscle-specific clocks preserves daily functions and prevents premature muscle aging. The research highlights that muscle clocks play a critical role in filtering harmful signals and integrating vital functions, influenced significantly by eating patterns.
Nature of epigenetic aging from a single-cell perspective
Dynamics of DNA methylation (DNAm) at both tissue and single-cell levels in mice is studied, comparing changes from early development to adult aging and incorporating single-cell RNA sequencing to better understand epigenetic aging. Epigenetic aging includes both co-regulated changes and significant stochastic elements.
The killifish germline regulates longevity and somatic repair in a sex-specific manner
Germline depletion in killifish enhances damage repair in females and extends lifespan and metabolic health in males. This suggests that germline manipulation can lead to sex-specific aging responses, challenging traditional views on evolutionary tradeoffs between reproduction and longevity.
APOE4 homozygozity represents a distinct genetic form of Alzheimer's disease
APOE4 homozygotes consistently show early and pronounced Alzheimer's pathology and biomarker levels, suggesting that APOE4 homozygosity constitutes a distinct genetic form of the disease.
3D genomic mapping reveals multifocality of human pancreatic precancers
Study showing widespread pre-cancerous mutations in the pancreas, with adults harbouring hundreds of precursors of pancreatic cancer.
Converting cell death into senescence by PARP1 inhibition improves recovery from acute oxidative injury
Inhibiting PARP1 in response to high oxidative stress shifts cells from death to a senescent state, aiding in tissue regeneration. This process, called CODIS, reduces mitochondrial Ca2+ overload and improves recovery in a mouse model of kidney damage.
Circadian tumor infiltration and function of CD8+ T cells dictate immunotherapy efficacy
The effectiveness of immune cells in controlling tumor growth and response to immunotherapy in cancers follows circadian rhythms, suggesting that incorporating time-of-day considerations could enhance clinical outcomes.
Single-cell senescence identification reveals senescence heterogeneity, trajectory, and modulators
SenCID, a machine learning tool, effectively identifies senescent cells in both bulk and single-cell transcriptomes, using a comprehensive dataset to categorize cells into six distinct senescence identities.
SGLT2 inhibition eliminates senescent cells and alleviates pathological aging
SGLT2 inhibitor canagliflozin reduces senescent cell accumulation and improves metabolic health in obese mice, distinctively outperforming insulin treatment. Canagliflozin not only lessens senescence in adipose tissue but also extends lifespan in mice with premature aging.
Published Literature Reviews, Hypothesis, Perspectives and more
The beginning of becoming a human
The 14-day post-fertilization stage marks the differentiation of soma from the germline and signifies key transitions in early embryogenesis, which recent scientific insights suggest may redefine organismal life's beginning, linking to broader biological processes such as aging.
Role of epigenetics in the regulation of skin aging and geroprotective intervention: A new sight
Epigenetic factors play a key role in skin aging by activating senescence programs that lead to structural and functional declines. Geroprotective medications aim to restore this epigenetic balance.
Psychogenic Aging: A Novel Prospect to Integrate Psychobiological Hallmarks of Aging
Psychological factors, crucial for healthspan and longevity, are often overlooked in aging frameworks. Psychogenic Aging research, a new biogerontology branch, explores how these factors affect longevity.
Job Board
Joao Pereira has two post-doc positions (two years) open at UAB (starting July/August) to study reproducibility in iPSC models, mostly organoids and assembloids! The other to study aging and Alzheimer’s! Starting salary 70k!
News and Media
Turn Biotechnologies Signs Global Licensing Agreement with HanAll Biopharma to Develop Eye and Ear Therapies
VitaDAO portfolio company Turn Bio signs a deal valued at $300 million USD to revolutionize age-related therapies worldwide.
Increased longevity will bring profound social change
An interesting piece from the Financial Times, discussing how with increased lifespans, people will have to work longer and pension systems will need to be transformed.
'Rejuvenating' mitochondria may help fight toxic proteins in Alzheimer's
Why is exercise good for you? Scientists are finding answers in our cells
Could delaying menopause boost women's health? 1 woman shares her story
Rapamycin: Could a simple pill add years to your life?
‘A lot of nonsense being spouted’: Nobel laureate Venki Ramakrishnan on the anti-ageing industry
Resources
Conferences
Conference season is upon us, which ones will you attend?
13-16th June, Dublin, Ireland
Aging and Rejuvenation Conference
8-10th July, Paris, France
26-30th August, Copenhagen, Denmark
4th - 6th September
9th International Cell Senescence Association (ICSA) Conference
7th - 9th November, Puerto Varas, Chile
Tweets of the Month
Dan Go: 5 simple ways to test how long you'll live
British Society for Research on Ageing
Ageing vs Aging
What's your default spelling?
And the Brits have it with “ageing” - absolutely no selection bias from the poll being answered by followers of the British Society for Research on Ageing…
Podcasts and Webinars
Check out the latest episode of The Sheekey Science Show, where Eleanor features the top 3 preprints from the current Longevist edition.
NewLimit Progress Update 2024
Some exciting updates on partial reprogramming from New Limit.
Longevity & Aging Series
NUS Medicine’s Healthy Longevity Webinar Series
Debates: How to Defeat Aging – $10K Prize! Aubrey de Grey VS Peter Fedichev
Longevity by Design: The Impact of DNA Damage & Lifestyle on Aging & Longevity Medicine with Dr. Morten Scheibye-Knudsen
The Biohacker Podcast Presents: The Longevity Revolution with Professor Nir Barzilai
Existential Threads, where curiosity meets deep thinking! Unravel the complex science of longevity and debunk popular health myths
The Optispan Podcast with Matt Kaeberlein:
Reversing Biological Age: Have we finally found the answer?
DON'T Take Resveratrol Until You Watch This Video
Interview with Adam Freund
Life sciences entrepreneur and executive with a Ph.D. in molecular and cell biology and 18 years of experience in research and drug development.
Founder and CEO, Arda Therapeutics - a biotechnology company taking aim at chronic diseases and aging by eliminating the pathogenic cells that drive these conditions.
What inspired you to enter longevity research?
For as long as I have been a scientist, I have been driven to study aging. It is one of, if not the, largest sources of suffering and loss. There is no reason to assume that our current lifespan is optimal: we live longer than our ancestors, yet no one suggests that shorter lifespans would be beneficial, and our descendants will hold the same perspective, whether they live two, three, or ten times longer than we do now. The biology of aging might appear intractable at first, but once you recognize that longevity is indeed modifiable - supported by ample experimental evidence across various species - why would you study anything else?
How has the field changed since you started?
The longevity field has matured significantly from focusing on individual pathways like telomere biology and sirtuins to embracing more complex, cell-centric approaches like cellular reprogramming and senolytics. Unfortunately, it hasn’t changed much in the way the matters most: intervention efficacy. We have characterized the changes that occur with aging more thoroughly, particularly at the levels of the transcriptome, epigenome, and increasingly, the cellular architecture of tissues, but the most effective interventions 20 years ago (calorie restriction, insulin/IGF inhibition, and mTOR inhibition) are still the most effective interventions today.
Other than your own, what do you think have been the biggest/important discoveries in the field?
I am most excited by interventions that have the potential to restore health, such as removing pathogenic cells or resetting epigenetic states, as compared to interventions that delay further decline. The former is superior to the latter in multiple ways - health impact, addressable market, ease of clinical development. It might be preferable to focus on delaying aging if it is substantially more feasible than reversing decline, but this is unlikely: preventing a system from degrading is often far more difficult than restoring it every so often. Restorative interventions are still relatively unproven, but I am excited by their potential.
What advice would you give to people currently working in longevity research?
Select projects based on their potential impact rather than mere curiosity; almost every topic becomes more interesting the more you learn about it. Evaluate interventions, don’t just compile another catalogue of age-related changes. Don’t assume that any species showing age-related decline has translational relevance; work with human data or closely related mammalian species, and hone in on conserved mechanisms by evaluating multiple species. Carefully nurture and protect your credibility.
Which aspect of longevity research do you think requires more attention?
The role of postnatal development programs in establishing the rate of aging. Time to sexual maturity is one of the best predictors of remaining lifespan across vertebrates, and the interventions that most reproducibly extend lifespan (e.g. insulin/IGF mutations) delay postnatal development. If developmental trajectories establish aging rate, it also explains why the heritability of lifespan is so low within species: purifying selection. The mutations that would most dramatically extend lifespan also dramatically delay postnatal development, leading to low viability and depleting those mutations from the population. Modulating developmental pathways in adulthood may provide longevity benefits without the detrimental effects.
Is ageing a disease?
Whether a condition is generally considered a disease vs “normal aging” is primarily based on the prevalence of that condition in the general population: an isolated group whose members all harbour presenilin-1 mutations would characterize Alzheimer’s as “normal aging” because it would be universal. This controversy, therefore, reduces to a question of reference point (shameless plug for a thought piece I wrote on this topic). Irrespective of how we label it, aging is a process that can and should be therapeutically altered.
You made some interesting academic discoveries related to cellular senescence when working in the late Prof. Judith Campisi’s lab - including how p38MAPK can regulate the SASP and that Lamin B1 loss is a biomarker of senescence. Could you tell us a bit about your research during this period and what your thoughts on senolytics in general are as a longevity therapy?
I joined the Campisi lab as the group was recognizing that senescent cells secrete pro-inflammatory factors. I was able to make a few contributions to our understanding of SASP regulation and in vivo biomarkers of senescence, and our work reinforced the concept that senescent cell depletion or inhibition could be an effective therapeutic strategy. Senolytics started gaining traction near the end of my graduate work, and while there has been a lot of effort put into their development, it is increasingly clear that in vitro models of senescence don’t have simple correlates in vivo. This has led to challenges with clinical translation and is one of the reasons I started Arda Therapeutics: there is a lot of evidence that pathogenic cell depletion has therapeutic potential, but starting from the senescence hypothesis may not be the most effective way to identify targets. At Arda, we use single cell data from human patients to identify pathogenic cell states, which has higher odds of clinical translation.
You then went on to identify a mechanism involved in telomerase trafficking, which if perturbed can prevent telomere elongation and cause disease. Please could you tell us about this?
For my postdoc, I went to Stanford to study telomere biology. I was interested in novel regulators of telomerase, so I developed a high-throughput RNA in situ hybridization assay and used it to perform a whole-genome screen to identify factors that altered telomerase RNA localization. This screen identified several novel telomerase regulators and clarified the mechanism of action of pathogenic mutations that cause the human condition dyskeratosis congenita. This turned into a few impactful publications, but by the end of my postdoc, I was convinced that, although telomeres play an important role in multiple aspects of human biology (dyskeratosis congenita, aplastic anemia, idiopathic pulmonary fibrosis, and cancer), telomere shortening is not a primary driver of aging. So I went looking for ways to re-orient my work towards aging biology.
Next you worked at Calico, what was that experience like?
I had always been interested in industry, but in 2014 there were not many opportunities to work on aging outside of academia. However, as I was getting ready for my next career move, Calico was announced – a longevity-focused biotech with a $1B budget. I immediately applied and was lucky enough to be hired as a principal investigator. I built a group developing new ways to quantify physiological aging, and I also initiated and was the scientific lead for Calico’s first therapeutic program targeting a conserved longevity pathway. This latter project snowballed into a full-fledged drug development program that is now in clinical trials, which was an incredible journey.
Currently, you are the founder and CEO of Arda Therapeutics, a company that aims to identify and eliminate pathogenic cells to prevent several diseases. What do you have in the pipeline and what can we look forward to next?
At Arda, we are taking aim at chronic diseases and aging by eliminating the pathogenic cells that drive these conditions. I have been incubating the idea of therapeutic cell depletion since my graduate work studying cellular senescence, but the more I studied senolytics, the more convinced I became that there was a broader opportunity to target other types of pathogenic cells. The difficulty was in identifying those cell states and targeting them with enough precision to be clinically viable. With the ascendance of single cell sequencing technology, which allows us to count cell states the way bulk transcriptomics counts mRNAs, we can finally turn this idea into a reality. At Arda, we use single-cell data from human patients to identify pathogenic cells and specific markers to target them. We then design therapies to eliminate these - and only these - cells. We are building a broad pipeline across multiple indications, starting with inflammation and immunology.
Outro
We appreciate you sticking with our research newsletter for another month and hope the content we curate is useful in helping you to keep up-to-date with all the exciting longevity-related developments.
In case you missed it, we leave you with the DeSci Berlin talk recordings from Day 1 and Day 2.
See you next month!
