Happy new year Vitalians and welcome back!
The Longevity field is starting the year strongly with new updated Hallmarks of aging, exactly 10 years after the original paper was published. So time to update your introduction slides with the figure we will see in every presentation for the next 10 years!
For the first month of the year we want to focus on one of the original and major hallmarks of aging - genome instability. DNA damage is a well-known driver of aging. It comes in many flavours - including single and double strand breaks, base modifications and crosslinking. DNA lesions are very common, occurring by the tens of thousands every day in every cell of our body. Luckily, we have evolved extremely efficient DNA damage repair machinery to cope with this. These mechanisms, while effective, succumb to age-associated decline, allowing DNA damage to accumulate in later life. Many environmental factors can contribute to DNA damage, from UV to toxins and radiation. Genome stability and epigenetics are tightly intertwined as we’ll see in a few of our hot pick papers this month. To demystify this and other DNA damage queries you may have, we have interviewed Prof Björn Schumacher, an internationally recognised expert in the area.
Longevity Literature Hot Picks
The rise of preprints has reduced the time it takes for new scientific discoveries to be disseminated to the world prior to publication in a peer-reviewed journal. For this reason we are introducing Preprint Corner to keep you even more up-to-date with the Longevity literature. 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! We will also be awarding a 500 $VITA prize to the review which receives the most upvotes out of the 6 preprints listed!
Reviewing bounty for these preprints available until 28th February, with upvotes counted and the prize winner announced 2 weeks later!
We are also excited to announce that voting is now open on Snapshot for our proposed overlay journal - The Longevist - aiming to be a curated collection of the most impactful longevity research every quarter, as voted on by a large body of Key Opinion Leaders.
Published Research Papers
Paternal, but not maternal, exposure to ionising radiation leads to embryonic lethality and the mechanisms are still unclear. Depletion of histone and heterochromatin proteins could reverse embryonic lethality by reducing histone methylation and enabling repair, ultimately improving offspring viability.
In the works for over 13 years, this massive study by Sinclair’s team presents an aging model - ICE (inducible changes to the epigenome) mice. DSB repair was reported to induce epigenetic deterioration earlier in life, which translated to physiological changes associated with aging. OSK reprogramming of ICE mice resulted in a lower epigenetic age.
Metabolism is highly associated with ageing, with many longevity interventions targeting key metabolic pathways. Here the authors show that yeast cells can exchange metabolites across generations with the nature of these interactions capable of determining cellular lifespan.
Patients with mitochondrial disease have increased resting energy expenditure, or hypermetabolism, which is thought to accelerate biological aging. Disrupting OxPhos (oxidative phosphorylation) either genetically or pharmacologically doubles the energy expenditure in the cell. More studies are needed to understand how these processes interact and link.
Decellularized and enzymatically digested extracellular matrix with pro healing properties was infused intravascularly in rats and pigs post injury. Substantial improvements were seen in ventricle volumes and wall-motion scores as well as molecular level changes indicating tissue repair processes suggesting translational potential for this technology to heal the heart “from the inside out”.
Sarcopenia is a major issue with the quality of life of older adults that does not have current treatment options. Inhibition of sphingolipid synthesis showed promise in the alleviation of age-related decline and improved functional parameters like exercise capacity and strength.
Lithium has been used in the clinic for many years as a management strategy for bipolar and similar psychiatric disorders. A number of recent studies have shown it can increase lifespan in multiple animal models but now a correlation with human longevity is found. An observational study with over half a million people reveals that lithium was linked to decreased mortality and 3.6 times lower chance of dying when compared to users on other antipsychotic drugs.
Whilst gene expression analysis has identified that many genes are differentially regulated with ageing, little has been known about the mechanisms driving these changes. This research shows that endogenous DNA damage can lead to RNA polymerase stalling which lowers transcriptional output and acts in a gene-length dependent manner.
It’s been around half a century since Denham Harman updated his Free Radical Theory of Ageing to implicate mitochondrial ROS production in driving age-associated decline. Here the authors show that increasing mitochondrial membrane potential can decelerate ageing and extend lifespan in nematodes. This is achieved with an optogenetic approach with a light-activated proton pump!
The study reveals how the lifetimes of proteins change in the aging brain. The altered rates of synthesis and degradation point to a metabolic adaptation prior to neurodegeneration.
Published Literature Reviews
Here we have the above mentioned updated hallmarks of ageing publication!
A complex interplay of numerous brain cell types is behind the Alzheimer’s dementia pathology. Cell type specific alterations and five main pathways were uncovered using single-cell profiling across five cell types. The highlighted pathways could be a important targets for therapeutic development.
Reproductive longevity is still largely understudied. The review summarises potential intervention that can prolong fertility in females and delay the onset of menopause which comes along with increased risk of a plethora of age-related diseases.
Concern about the predictive value of testing therapeutics in lower life forms is raised after surprisingly little predictive value for identifying drugs in worms that extend lifespan in mice. While not conclusive in making C. elegans obsolete as a model, the study raises the question of model accuracy and relevance to translation to humans.
Clinical Trial Updates
VitaDAO is looking for a relentless, resourceful, well-organized, and dynamic person to advance the projects in our portfolio and spin them out as a co-founder or EIR.
The new “Microbiome and Metabolism” research group studies the metabolic crosstalk between cells in health and disease, with particular focus on aging.
PhD positions available at the Computational Biology group at the FLI - a multi-disciplinary group composed of bioinformaticians, statisticians, biochemists, and biologists. Projects focus of using machine learning to uncover more about epigenetic changes during cancer and aging. Applications accepted until January 31.
Postdoctoral positions are open at the McAlpine lab, Icahn School of Medicine at Mount Sinai. If you want to explore the role of immune cells in cardiovascular and neurodegenerative diseases, please reach out to the group.
Gero is looking for a data scientist to help them in their mission to develop new therapeutics and biomarkers against aging and complex diseases.
Retro is now offering a Graduate Research Fellowship, which is a great opportunity for undergraduates who do not want to do a PhD, but want to become scientists. Retro works on partial reprogramming, blood factors and autophagy for cellular rejuvenation.
The study with more than 800 patients (early Alzheimer’s) showed Leqembi slowed physical and mental decline by 27% over an 18-month period. The average cost of the drug will be $26,500 per year. Eisai defended the price based on the drug’s value to society, but it is likely to cause concern and draw scrutiny because of its potential wide use.
Dr. Greene Draws on a Deep Reservoir of Experience as a Venture Capitalist, Impact Investor and Biotech Entrepreneur
After a dispute resulting in the resignation of editors-in-chief from the journal Aging Cell, the former editors have now founded a new journal - Aging Biology - publishing research in the field of aging.
Big pharma dipping its toes in longevity with Peter Fedichev’s Gero collaboration
Conferences and Webinars
The first ever DeSci London Conference was a resounding success! Hosted over 2 days in January at the esteemed Francis Crick institute in London, it featured talks from the who's who of the DeSci world, with Ethereum founder Vitalik Buterin even dialling in to share his thoughts on DeSci. Live recordings from the conference coming soon….
Podcasts and Videos
Longevity Tweet of the Month
Sebastian J. Hofer:
“I asked #ChatGPT how to achieve #healthy #aging. Can't argue with its reasoning. Next, I asked which interventions should be combined to achieve maximal #lifespan extension in mice (see comment). So, who will try this? And who will fund it?
Follow the link to see ChatGPT’s response!
João Pedro de Magalhães hosts an educational and information resource on the science of aging: https://www.senescence.info/
A great resource showing Longevity biotech companies and their investors: https://agingbiotech.info/investorsXcompanies/
Interview with Prof Björn Schumacher
Prof Schumacher is a director of the Institute for Genome Stability in Ageing and Diseases (IGSAD) at CECAD Research Centre of the University of Cologne, a president of the German Society for Ageing Research (DGfA), a Vice President of the German Society for DNA Repair (DGDR) and serves on several editorial boards.
What inspired you to enter longevity research?
That happened during a biology class at high school, when I realised how little we knew about our own biology. We are all subject to the invariable fate of ageing but we don’t understand that process at all. I knew I had to study the biology of ageing even though that wasn’t even a research field back then. So I decided to study biology and over time I would find out what would be the most important aspects of biology to study in order to illuminate ageing.
Which of the current theories of ageing do you think are the most convincing?
The theory of ageing is pretty much settled. It is really clear that ageing is a consequence of the lack of natural selection to indefinitely maintain the soma after the genes have been passed on to the subsequent generation. This is reflected in Tom Kirkwood’s disposable soma theory but also in the mutation accumulation and the antagonistic pleiotropy theories. The soma is only the vehicle for the indefinite maintenance of the germline throughout the generations.
How has the field changed since you started?
The field has really expanded phenomenally in the past two decades. When I started there was some telomere research that was super exciting and the genetic work in C. elegans that was really driven into the spotlight by Cynthia Kenyon. The most important development in the field over the past two decades was that it attracted scientists from diverse fields. This has made the field much stronger because ageing is affecting about every biological process.
What mistakes do you think the longevity field has made?
Some of those big claims and great expectations have had an inflationary effect on expectations. “Ageing reversal”, “rejuvenation” are big words with very little factual biology to back it up as true physiological reversal of ageing. While it is great to inspire with exciting concepts, it is also important to realise that ageing is complex and we have only grasped the tip of the iceberg.
Other than your own, what do you think have been the biggest/important discoveries in the field?
There were some real breakthrough discoveries. Conceptually, Tom Johnston’s and Cynthia Kenyon’s discovery of genetic mechanisms of ageing in the early 1990s, and Jan Hoeijmaker’s demonstration that DNA repair defects promote pretty much the entire set of ageing phenotypes in the early 2000s were really ground-breaking. The transformative discoveries of stem cell reprogramming by Shinya Yamanaka’s and Steve Horvath’s pioneering work on ageing clocks probably have the most practical consequences when it comes to interventions.
What advice would you give to people currently working in longevity research?
It is very important to study ageing with open eyes and receptive minds. The biological processes that impact ageing are intimately interconnected. We must further thrive to understand the physiology of ageing, which is why organisms are so important as study models. Often people stay within their own silos and are ignorant of other aspects of biology.
Which aspect of longevity research do you think requires more attention?
I think the integration of model organism and human data need to be much more proactively pursued. Cancer research has shown us how difficult it is to transfer interventions that work in mice to humans. Transferring geroprotective interventions will be hugely more difficult because ageing is an integration of long-lasting trajectories that are impacted by all those distinct genetic variants and epigenetic effects that each individual human is subjected to but are unaccounted for in laboratory animals.
Is ageing a disease?
Ageing is a physiological process but not a disease. However, it is the cause of all chronic diseases for which age is the primary risk factor. Therefore, we need to target the ageing process itself to prevent age-related diseases. Given the demographic change this is our only option for a future with 2 billion elderly whose active participation in society to a significant degree depends on their health. It is as urgent as fighting climate change to fight the multimorbidity that is affecting a growing proportion of the population. We need to boost ageing research now!
Can you discuss the relative importance and potential causative relationship between DNA damage and epigenetic alterations in aging with examples from your own work?
DNA damage is occurring all the time. Our genome is inherently unstable and requires constant repair. The DNA in our cells not only encodes all information but in contrast to all other molecules, the genome cannot be replaced. The response to DNA damage affects about every process in the cell. We found that the longevity assurance mechanisms that regulate lifespan respond to DNA damage and increase the tolerance of DNA damage accumulation. Epigenetic mechanisms are also a very important regulatory response to DNA damage. We recently found that epigenetic regulators mediate the recovery of protein homeostasis following the repair of DNA damage that interferes with transcription. This finding links three causal hallmark processes of ageing: Genome instability, epigenetics, and protein homeostasis.
Although there has been a lot of interest in epigenetic aging in recent years, there has been less excitement and success stories around DNA damage and repair. Why do you think this is the case? What are the biggest challenges in the field?
There are two important factors here: One is the complexity of the DNA repair machineries and the second one is technology. Epigenetic modifications are very easy to detect and quantify. DNA damage is much harder to detect because of the sheer number of distinct lesion types. There has been tremendous progress just in the past year to detect mutations, which are consequences of DNA damage and it has become clear that the rate of somatic mutations is highly correlated with the lifespan of a species. Despite the complexity, targeting ageing at the most fundamental level involves developing strategies for augmenting genome stability.
What do you think are the most viable therapeutic avenues for targeting DNA damage?
For human ageing DNA repair is absolutely fundamental as the pathologies of congenital disorders caused by mutations in DNA repair genes clearly demonstrate. DNA repair mechanisms are as complex as the plethora of lesion types in the genome. We are working on mechanisms that can augment the entire set of DNA repair machineries. The key lies in the germ cells, because they repair far more effectively than somatic cells as their genomes are maintained indefinitely. Our concept is to confer germline-like repair efficiency to somatic cells.
And how likely are they to increase healthspan and lifespan from what we know in animals?
The realization that both healthspan and lifespan could be increased in organisms is one of the defining concepts of ageing biology. The plasticity of lifespan is quite distinct in species. The nematode C. elegans is the gift that keeps on giving because of its vast plasticity of lifespan, which is an adaptation to the boom and bust economy in the ecological niche of this species. Amid ample food they reproduce exponentially and upon starvation they can outlive a normal developmental cycle at least ten times. Such a degree of plasticity doesn’t exist in more complex animals. Nonetheless, some of the centenarians are healthy until the last year before their death at very old age. So also in humans, it is perfectly possible to extend healthspan to the 120 years that are currently thought to be the upper limit of human lifespan. This would be truly transformative for human health and prerequisite for a demographically changed society that is inclusive and harmonious.
Thank you for staying with us till 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.