Introduction
Welcome back Vitalians and please join us in congratulating The Fission Pharma team for passing the Snapshot vote to receive VitaDAO funding!
Fission Pharma is developing a protein-protein interaction inhibitor that cuts the link between chronic inflammation and mitochondrial dysfunction to treat multiple age-related diseases and extend human lifespan.
In this issue we will be exploring the Boundaries of Aging and what goes beyond the Established Hallmarks.
Aging is a universal process that affects all living organisms. In 2013, a seminal paper was published which sought to categorize the aging process by establishing a number of common hallmarks of aging. These hallmarks, which include genomic instability, telomere attrition, mitochondrial dysfunction, and cellular senescence, among others, provide a robust framework for studying the biological underpinnings of aging. A follow-up paper was published in 2023 which introduced more hallmarks of aging, however, as our understanding deepens, it becomes increasingly clear that these hallmarks may not fully capture the entirety of the aging process. This realization has spurred scientists to both refine existing theories and explore new frontiers in aging research.
As the field of geroscience progresses, researchers are beginning to identify additional factors that might influence aging but are not encompassed by the current hallmarks.
The ongoing updates to the aging hallmarks reflect the dynamic nature of scientific understanding. As researchers uncover more about the complex interactions between different biological systems, it becomes essential to revise and expand the aging framework. This includes integrating systems biology approaches to understand the interactions between various hallmarks, rather than viewing them in isolation.
This topic was inspired by some discourse in Longevity Twitter/X so don’t miss our Tweet of the month section for some spicy takes. And as always make sure you get to the end to find this month’s interview with Prof. David Vilchez where we discuss a number of innovative approaches he employs in his lab to understand the aging process.
Longevity Literature Hot Picks
Preprint Corner in collaboration with
The Longevist is a preprint overlay journal spotlighting the most promising longevity studies each quarter.
The VitaDAO community recently voted (almost) unanimously to continue funding The Longevist through 2024. So let’s kick off 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!
Long-term fasting remodels gut microbial metabolism and host metabolism
Analog epigenetic cell memory by graded DNA methylation
Comprehensive Whole Genome Sequencing Reveals Origins of Mutational Signatures Associated with Aging and Temozolomide Chemotherapy
Age-Invariant Genes: Multi-Tissue Identification and Characterization of Murine Reference Genes
Published Research Papers
Small extracellular vesicles from young plasma reverse age-related functional declines by improving mitochondrial energy metabolism
Young blood's small extracellular vesicles (sEVs) rejuvenate old tissues, improving molecular, mitochondrial, cellular, and physiological aspects in mice. They extend lifespan, reduce senescence, and enhance tissue function by altering proteomes and boosting mitochondrial metabolism via PGC-1α.
Epigenetic age oscillates during the day
Epigenetic age predictions show a 24-hour cycle, with the youngest and oldest estimates around midnight and noon. Testing 17 clocks revealed that 13 exhibit daily oscillations, suggesting the importance of time-of-day in obtaining accurate epigenetic age estimates.
Spatiotemporal transcriptomic changes of human ovarian aging and the regulatory role of FOXP1
The study uses single-cell RNA sequencing to analyze human ovarian aging, identifying molecular changes in eight ovarian cell types. It highlights the DNA damage response in oocyte aging and the regulatory role of FOXP1, which declines with age and impacts ovarian function, suggesting new targets for therapy.
A lipidome landscape of aging in mice
Explores aging's impact on lipid metabolism using lipidomics across mouse life stages, the findings suggest age-related changes in fatty acids and a link between sulfonolipids and the microbiome. In male kidneys, certain glycolipids were enriched in aged mice, with enzymes identified that could be targets for reducing sex-specific kidney disease risks.
Doxycycline decelerates aging in progeria mice
Doxycycline (DOX) extends lifespan and alleviates aging symptoms in a mouse model of progeria by improving nuclear structure, reducing cellular aging, and decreasing IL6 inflammation. DOX also counteracts harmful protein acetylation, showcasing its potential as a therapy.
Inhibition of S6K lowers age-related inflammation and increases lifespan through the endolysosomal system
Rapamycin suppresses aging by inhibiting TORC1-S6K signaling, which, when activated, disrupts cellular health and increases inflammaging. This pathway's effects, mediated by Syntaxin 13 and impacting the IMD pathway, are observed from flies to mammals.
BCAA-nitrogen flux in brown fat controls metabolic health independent of thermogenesis
The study reveals a novel role for brown adipose tissue (BAT) in metabolic health, beyond its known function in thermogenesis. Impairing BAT's mitochondrial catabolism of BCAAs leads to systemic insulin resistance without affecting body weight or energy expenditure. BAT uses these amino acids to synthesize non-essential amino acids and glutathione, mitigating oxidative stress and supporting insulin signaling.
A concerted increase in readthrough and intron retention drives transposon expression during aging and senescence
Increased transposon and intron expression in aging is linked to transcriptional readthrough and intron retention. Analysis of RNA-seq datasets shows these transcriptional defects escalate with age, particularly in humans, driving transposon activity.
U-shaped association between sleep duration and biological aging: Evidence from the UK Biobank study
A UK Biobank study of 241,713 participants shows a U-shaped link between sleep duration and aging. Both short (≤5 hours) and long (≥9 hours) sleep durations correlate with accelerated aging compared to 7 hours, mediated by biomarkers like cystatin C and GGT.
Dietary restriction extends lifespan across different temperatures in the fly
The effect of dietary restriction (DR) on lifespan in Drosophila melanogaster across temperatures (18°C and 21°C) is examined, using a strain known to benefit at 25°C. Findings show DR consistently extends lifespan, regardless of temperature.
NMR metabolomic modeling of age and lifespan: A multicohort analysis
Nuclear magnetic resonance (NMR) metabolomic age models were assessed using blood samples from approximately 31,000 UK and Finnish individuals. While the correlation with chronological age was moderate, these models effectively predicted mortality and diseases like cardiovascular disease.
Identification of senescent, TREM2-expressing microglia in aging and Alzheimer’s disease model mouse brain
High-throughput mass cytometry identified distinct microglial populations in Alzheimer's disease using the 5×FAD mouse model. Senescent microglia expressing TREM2 differ from disease-associated microglia (DAM) and are linked with cognitive decline. TREM2-null mice had fewer senescent microglia, and treatment with senolytic ABT-737 improved cognition and reduced brain inflammation.
N, N-Dimethyltryptamine, a natural hallucinogen, ameliorates Alzheimer’s disease by restoring neuronal Sigma-1 receptor-mediated endoplasmic reticulum-mitochondria crosstalk
DMT, a natural psychedelic and Sig-1r agonist, improves cognitive function, reduces Aβ accumulation, and restores Sig-1r levels in 3×TG-AD mice. It enhances ER-mitochondria interactions, calcium dynamics, and mitochondrial function.
Methylation entropy landscape of Chinese long-lived individuals reveals lower epigenetic noise related to human healthy aging
Long-lived individuals (LLIs) show suppressed epigenetic noise compared to controls. LLIs have specific genomic regions with lower methylation entropy, mainly in promoters, impacting aging-related disorder heritability. Neutrophils maintain this unique epigenetic stability.
Published Literature Reviews, Hypothesis, Perspectives and more
The senescence-associated secretory phenotype and its physiological and pathological implications
This review explores how the senescence-associated secretory phenotype (SASP) can both positively and negatively affect our body in various health and disease conditions, as well as its influence on our overall health over time. Additionally, it discusses how the SASP can be used as a health indicator and how substances that block SASP might be used to treat cancer and other conditions related to aging.
Rejuvenating aged stem cells: therapeutic strategies to extend health and lifespan
This review examines the latest research on methods that enhance the regenerative abilities of aged stem cells in mammals. The authors emphasize that rejuvenating these cells is a key strategy for maintaining overall body health as we age and discuss new techniques that could potentially extend both health and longevity.
Job Board
Payel Sen is looking to recruit a postdoc to study muscle stem cell aging at the NIA. Interested candidates with expertise in chromatin biology, genomics and stem cell biology are encouraged to apply directly to payel.sen@nih.gov.
Xu Chen is hiring an NIH-funded postdoctoral fellow position at http://xuchenlab-ucsd.org to study tau pathophysiology in Alzheimer's disease and related dementia - more details here.
Dena Dubal is hiring postdoctoral fellows to study the longevity factor klotho and brain resilience in aging and Alzheimer's – using cellular, molecular, behavioral, and bioinformatic approaches. DM on Twitter/X if interested!
The Gurkar lab at the University of Pittsburgh, focusing on aging and DNA repair, is hiring for 3 positions: Lab Manager/Research Specialist, Mouse-house Technician, Post-doctoral Fellows. If interested please send your CV with name, email, and phone numbers of references to agurkar1@pitt.edu.
A number of open positions at the Buck Institute are available. Check out their website to see if you can find a match: from postdoc and masters positions to admin and even a CFO.
Shift Bio are currently hiring for a Machine Learning Research Scientist to build and improve our cell simulation models, and work on algorithms that help us to prioritise potential rejuvenation interventions.
News and Media
VitaDAO-backed Rubedo lands $40m to advance senescence-targeting therapeutics into clinical trials
Science is closing in on the frailties of old age
Beiersdorf and Rubedo announce multi-year partnership to develop breakthrough anti-aging solution
Vitalia: Living the Longevity Dream
A Honduran tourist island has attracted a lot of people interested in longevity.
Your Dog Will Have an Anti-Aging Drug Before You Do
NASA discovered bacteria that wouldn't die. Now it's boosting sunscreen
New Research Suggests That Cutting Exposure to Common Chemicals Could Slow Aging
Resources
Problem choice and decision trees in science and engineering with accompanying Tweet.
Conferences
Who’s excited for conference season? It’s that time of the year again. Have you booked your flights?
Gordon Research Conference (GRC)
2-7th June, Barcelona, Spain
American Aging Association Annual Meeting (AGE)
2-5th June Madison, Wisconsin USA
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
Here are some spicy tweets relating to the hallmarks of aging:
https://twitter.com/MartinBJensen/status/1784244762842992906
https://twitter.com/dweinkove/status/1784246336574894112
And some other interesting picks of the month:
Food for thought on mitochondrial transplantation
Why Karl Pfleger is cautiously optimistic on rejuvenation progress
Podcasts and Webinars
Longevity & Aging Series
NUS Medicine’s Healthy Longevity Webinar Series
Episode 2 of the Longevity Acceleration Podcast is out-
they speak to Reason of Repair Biotechnologies about the gene delivery problem, the prospects for repairing aging damage, and more. Check it out!
Dr. Brad Stanfield discusses what is the ‘best’ diet to prevent disease and live a long, healthy life?
The Sheekey Science Show has a Theme Tune!
Longevity by Design, Produced by InsideTracker: The Impact of DNA Damage & Lifestyle on Aging & Longevity Medicine with Dr. Morten Scheibye-Knudsen
Biohackher: The Longevity Revolution with Professor Nir Barzilai (libsyn.com)
Interview with Prof. David Vilchez
Prof. David Vilchez is a distinguished researcher at Cologne Excellence Cluster on Aging and Aging-Associated Diseases, focusing on the intersection of proteostasis, aging, and stem cell functionality. His innovative research employs a combination of iPSC-based disease modelling, genetic studies in C. elegans, advanced proteomics, and plant research to explore cellular and organismal responses in age-related diseases.
What inspired you to enter longevity research?
Since my undergraduate studies, I have been passionate about the complexity of the nervous system and neurodegenerative diseases. During my PhD, I focused on a rare disease linked to the accumulation of aggregates in neurons and deficits in proteolytic systems. When I was searching for labs to conduct my postdoc, I came across a recent paper from Andy Dillin’s lab in C. elegans. They discovered that longevity mechanisms, such as the reduced insulin pathway, can prevent the accumulation of pathological aggregates associated with Alzheimer’s disease. I was fascinated by the potential of C. elegans as an organismal model for neurodegenerative diseases involving protein aggregation. Joining Andy’s lab opened a new horizon for me, and I became very interested in how we can slow down aging for multi-disease prevention. This led us to the idea of studying the immortality of pluripotent stem cells and applying these mechanisms in post-somatic cells, such as neurons, to prevent diseases.
Which of the current theories of ageing do you think are the most convincing?
I believe that all current theories of aging are plausible. It is crucial to recognize the interconnectedness between these theories and remain open-minded to new findings that can either update or introduce completely unexpected theories. For instance, the disposable soma theory of aging postulates that organisms invest resources to protect their germline, leading to somatic tissue deterioration and aging. This has been supported by many studies, including work from our laboratory. However, we have recently demonstrated that this not always the case. For instance, advantageous conditions such as moderate cold temperature can delay germline aging, leading to extended fertility. In turn, the rejuvenated germline release longevity signals that maintains somatic fitness at cold temperature, a process that coordinates extended fertility and long lifespan without sacrificing any of these features.
How has the field changed since you started?
Since I began working in the aging field during my postdoc, I have witnessed significant evolution. One notable positive change is the increasing number of labs joining the field, bringing new perspectives crucial for advancing longevity research.
What mistakes do you think the longevity field has made?
There are certainly areas where approaches could have been adjusted, but I would not classify them as mistakes. Like any other field, aging research has progressed based on the prevailing theories, available knowledge, and methodologies at the time. As a field that is continuously evolving, it's important to remain open to exciting and unexpected discoveries that will shape our understanding in the future.
Other than your own, what do you think have been the biggest/important discoveries in the field?
The initial discoveries that modulating pathways such as insulin signaling can extend longevity were paradigm-shifting, demonstrating that aging is a regulated process. In my opinion, a recent key finding is the possibility of delaying aging through partial reprogramming strategies.
What advice would you give to people currently working in longevity research?
My advice is to remain open-minded and expect the unexpected, which holds true for any research field.
Is ageing a disease?
Aging is a natural and progressive stage in the life cycle of any animal. However, aging is a primary risk factor for multiple diseases. The key focus lies in the potential to delay aging to enhance our quality of life and prevent multiple diseases simultaneously.
Many researchers focus on the established hallmarks of aging as central mechanisms driving the aging process. In your view, do these hallmarks comprehensively account for the complexity of aging, or should the scientific community also explore beyond this framework? Would you focus on other overlooked processes that might be equally or more significant?
The hallmarks of aging provide a valuable framework for understanding the aging process. However, aging is a multifaceted phenomenon, and it's essential for the scientific community to explore beyond these established hallmarks to fully comprehend its complexity. We must remain open to the possibility of updating these hallmarks and discovering new, unexpected factors that contribute to aging. For instance, the recent updates to the hallmarks of aging demonstrate this evolving understanding. In our laboratory, we are committed to exploring overlooked processes that may be equally or more significant, guided by the insights gained from our results and the findings from other laboratories.
Your lab has studied how certain plant proteins might have potential applications in neurodegenerative diseases. Do you think we can learn more from the plant kingdom that could be impactful for human aging?
The research in our lab on certain plant proteins and their potential applications in neurodegenerative diseases has opened up intriguing possibilities. The longevity of stem cell reservoirs in plants like the Sequoia tree, which can remain active for over 2,000 years, highlights the remarkable biological processes in the plant kingdom. We are certainly open to the idea that insights from plant biology could lead to novel approaches in preventing human aging. Currently, we are actively exploring this hypothesis as part of our ongoing research efforts.
What role does temperature play in the aging process? We know about heat shock and proteostasis but your recent paper has highlighted a protective mechanism activated by cold temperatures. Can we use acute temperature shifts or mild but constant variation of body temperature to modulate the aging process?
Temperature plays a crucial role in the aging process for both poikilotherms and homeotherms. While we are familiar with the effects of heat shock and proteostasis on aging, our recent research has shed light on a protective mechanism activated by moderate cold temperatures. We have found that mild cold temperature not only extends lifespan but also delays reproductive aging in C. elegans. Additionally, it can delay the accumulation of pathological protein aggregates in both C. elegans and human cell models.
These findings are particularly significant given the increasing incidence of age-related diseases in our population. They offer a new perspective on how to delay or prevent these disorders. In our laboratory, we primarily focus on maintaining mild and constant low temperatures throughout the entire adult life of C. elegans. However, we have also explored shorter periods (24 hours) of cold temperature in human cells. So it will be fascinating to assess whether short periods of mild cold temperature can also have beneficial effects at the organismal level.
While acute temperature shifts are not our current research focus, further studies in this area are needed to explore their potential impact on the aging process and therapeutic applications.
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. See you next month!
