Welcome back to our monthly newsletter! This month we are excited to bring you an interview with Dr. Marco Demaria who has made some significant contributions to our understanding of cellular senescence.
For those of you not well-versed in senescence, here's a little intro….
It used to be thought that given the correct culture conditions human cells would be able to proliferate indefinitely, however some pioneering experiments from Leonard Hayflick showed this was not the case and eventually cells would permanently stop dividing - this phenomenon was coined 'cellular senescence'. Traditionally thought of as a tumour suppressor mechanism, research has shown that senescence is involved in a range of functions from development, to wound healing (Marco Demaria!). However, senescent cells have also been shown to elicit a pro-inflammatory response (senescence-associated inflammatory response - SASP) thought to attract immune cells to clear them. But as we age, an increase in the number of cells entering senescence, coupled with a decline in the ability of the immune system to clear them, leads to an accumulation of senescent cells and a chronic SASP which can paradoxically lead to a pro-tumourigenic environment and is associated with numerous diseases. Genetic and pharmacological removal of senescent cells has been shown to attenuate age-related diseases and extend lifespan in mouse models. Efforts to target/suppress senescent cells in humans (senolytic/senotherapy) have therefore gained significant traction both in academia and industry.
For some up-to-date perspectives and cutting edge research on cellular senescence (as well as other topics) check out our hot picks below!
Longevity Literature Hot Picks
So many fascinating papers were published this month that, in addition to our hot picks, we’ve had to include a Further Reading section for you at the bottom of this issue - enjoy!
Nuclear morphology is a deep learning biomarker of cellular senescence
https://www.nature.com/articles/s43587-022-00263-3
A universal marker for cellular senescence has yet to be discovered. However, research from the Scheibye-Knudsen laboratory has utilised machine learning to detect senescent cells by nuclear morphology alone, with up to 95% accuracy in human fibroblasts, when compared to a cocktail of canonical senescence markers.
Cellular senescence: the good, the bad and the unknown
https://www.nature.com/articles/s41581-022-00601-z
Senescence and cancer — role and therapeutic opportunities
https://www.nature.com/articles/s41571-022-00668-4
Cellular senescence: a key therapeutic target in aging and diseases
https://www.jci.org/articles/view/158450#.YuhXTn-A0M4.twitter
Cellular senescence and senolytics: the path to the clinic
https://www.nature.com/articles/s41591-022-01923-y
Above are 4 reviews on senescence which each give unique perspectives ranging from our mechanistic understanding of the senescent phenotype, to its role in cancer and other diseases, to how we can target senescent cells and efforts to translate this to the clinic.
Mitochondrial ROS promotes susceptibility to infection via gasdermin D-mediated necroptosis
Dysregulated mitochondrial homeostasis can result in switching cell death modalities and direct immune outcomes. The inflammasome is activated in Lrrk2 gain of function macrophages. Mitochondrial ROS directs the pore-forming protein gasdermin D to mitochondrial membranes, leading to inflammasome activation.
Naked Mole-Rat Hyaluronan Synthase 2 Promotes Longevity and Enhances Healthspan in Mice (under review)
https://papers.ssrn.com/sol3/papers.cfm?abstract_id=4185135
High molecular weight hyaluronic acid (HMW-HA) is known to aids cancer resistance and possibly healthspan the naked mole-rat. Overexpressing hyaluronan synthase 2 resulted in lower cancer incidence, increased lifespan and improved healthspan, likely by affecting inflammation, response to ROS and enhancing the gut barrier with age.
Warburg-like metabolic transformation underlies neuronal degeneration in sporadic Alzheimer’s disease
https://www.cell.com/cell-metabolism/fulltext/S1550-4131(22)00313-8#.Yv_gSYZ1KU8.twitter
With the aim to study the drivers of Alzheimer’s disease, the study identifies a metabolic switch to aerobic glycolysis in induced neurons from AD patient fibroblasts. Cancer associated PKM2 isoform was essential for this change and if chemically modulated to prevent nuclear translocation, neuronal metabolism was restored.
Astrocytic traffic jams in the aging brain
https://www.nature.com/articles/s43587-022-00270-4
Three distinct clusters of astrocytes were identified in aged mice hippocampi. One of them is novel and previously unrecognised, which was characterised with disrupted proteostasis. This contributed to a defective astrocyte morphology, synaptic maintenance and protein trafficking.
Cyanidin-3-O-glucoside promotes stress tolerance and lifespan extension of Caenorhabditis elegans exposed to polystyrene via DAF-16 pathway
https://www.sciencedirect.com/science/article/abs/pii/S0047637422001051?via%3Dihub
Microplastics are a growing pollutant in our environment and food chain. The effects and toxicity of a common microplastic polystyrene (PS) were explored in worms. As expected PS was toxic and decreased lifespan, which was mitigated by cyanidin-3-O-glucoside (C3G) treatment.
Chill out: environmentally relevant cooling challenge does not increase telomere loss during early life
https://www.sciencedirect.com/science/article/pii/S0016648022001332?via%3Dihub
Stressors early in life can have both positive (damage resistant) or negative (damage promoting) effects later in life. Timing and context is crucial for deciding the effect of environmental challenges. In birds, cooling has no effect on telomeres, but brood size and growth rate during nesting stage affect telomere shortening.
Dose-response association between the daily step count and all-cause mortality: A systematic review and meta-analysis
https://www.tandfonline.com/doi/full/10.1080/02640414.2022.2099186
Getting in your 10,000 steps a day has become as popular a health target as eating your “5 a day” of fruit and vegetables. However, metrics such as these are often criticised for being too arbitrary. Now a meta-analysis of all-cause mortality shows a non-linear inverse relationship between the number of daily steps and chances of dying - so keep moving!
Measuring biological aging in humans: A quest
https://onlinelibrary.wiley.com/doi/10.1111/acel.13080
Biomarkers to quantify biological age are required in order to test the efficacy of interventions aimed at delaying the onset of age-related diseases. This review highlights the known hallmarks of ageing, their link to morbidity and how being able to quantify biological age could lead to a therapeutic revolution.
Promotion of Hair Regrowth by Transdermal Dissolvable Microneedles Loaded with Rapamycin and Epigallocatechin Gallate Nanoparticles
https://www.mdpi.com/1999-4923/14/7/1404
Rapamycin - a drug which inhibits mTOR (one of the central regulators of metabolism) has been shown to be able to extend lifespan in numerous model organisms. New research shows that injection of rapamycin-containing nanoparticles can increase hair growth in mice in just 7 days, evidenced by increased hair follicle density and higher hair shaft growth rate.
Clinical Trial Updates
Unity Biotechnology
Unity announced positive data from their Ph 2 BEHOLD study of UBX1325 in diabetic macular edema. The 12- and 18-week results are a promising step in validating their senolytic platform and supports the potential of UBX1325 in retinovascular diseases.
New / Active Rapamycin Human Clinical Trials (related to Aging)
https://www.rapamycin.news/t/new-active-rapamycin-human-clinical-trials-related-to-aging/2650
News
Peter Adams and collaborators at UCSD been awarded $10.6M from @NIH_CommonFund to join SenNet, an initiative to create a comprehensive atlas of how and where aging cells accumulate.
Read more: https://bit.ly/3vVCTwd
LongevityTech.fund II launches – now accepting new investors
https://longevity.technology/news/longevitytech-fund-ii-launches-now-accepting-new-investors/
BioAge Partners With Age Labs to Decipher Healthy Longevity Using Samples and Data From a Preeminent Northern European Biobank
Longevity Resources
Age-related Disease Spreadsheet
https://docs.google.com/spreadsheets/d/19wPcWmW868mmMvugL_N4DJjMLt0WpnLB3o7D6RaiGP8/edit#gid=0
The Norn Group has curated this useful resource containing an overview of age-related diseases with data on biology, epidemiology, clinical landscape, animal models and market research!
Articles
Decentralized investor communities gain traction in biotech
https://www.nature.com/articles/s41587-022-01459-z
Epigenetic ‘Clocks’ Predict Animals’ True Biological Age
https://www.quantamagazine.org/epigenetic-clocks-predict-animals-true-biological-age-20220817/
As billionaires race to fund anti-aging projects, a much-discussed trial goes overlooked
https://www.statnews.com/2022/08/09/anti-aging-projects-funding-much-discussed-trial-overlooked/
Martin O’Dea: longevity is burning bright in Ireland
https://longevity.technology/news/martin-odea-longevity-is-burning-bright-in-ireland/
40,000 pet dogs, one big question
https://www.theatlantic.com/science/archive/2022/07/senior-dog-aging-project-brains/671008/
These Six Biotechs are Winning the Race to Get AI-Designed Drugs to the Clinic
The Opposite of Death Is Youth
https://tomhyde.substack.com/p/the-opposite-of-death-is-youth?r=hf6xj&utm_medium=ios
With advances in medicine, could 80 become the new 40?
https://www.cbc.ca/radio/spark/with-advances-in-medicine-could-80-become-the-new-40-1.6427495
Lengthening a woman's fertility may extend her life as well, research finds
https://edition.cnn.com/2022/08/20/health/extending-fertility-aging-life-itself-wellness/index.html
Book
Methuselah's Zoo: What Nature Can Teach Us about Living Longer, Healthier Lives
Book by Steven N. Austad
Newly published book delving into the biology of long-lived organisms and what they can teach us about the biology of ageing. Check out an article written by the author Steven N. Austad in ‘The Atlantic’:
https://www.theatlantic.com/science/archive/2022/08/clams-bivalves-long-lifespan-ming/671107/
Also, a review of the book by Prof. Charles Brenner:
Upcoming conferences
Longevity Summit Dublin 2022
September 18th-20th, Dublin
https://longevitysummitdublin.com/
Longevity Investors Conference
September 28-30, 2022, Gstaad, Switzerland
https://www.longevityinvestors.ch/
7th International Cell Senescence Association (ICSA) Conference
September 29th - October 1st, Groningen
https://www.icsa2022groningen.nl/
The Rejuvenation Startup Summit
October 14-15, 2022, Berlin, Germany
https://forever-healthy.org/summit/
2nd VitaDAO Crypto meets Longevity Symposium
October 20th, Online
Check out our 1st symposium here: https://www.youtube.com/watch?v=GJ-rJAfjhBE
The Longevity Summit 2022
December 7th-8th, Buck Insitute for Aging, US
Funding Opportunities
Life Extension Ventures
A new $100 million fund that is focused on life extension for "people and planet."
Job board
Research Associate Position, Ochre Bio, New York, US
Ochre Bio works on chronic liver health challenges, from reducing cirrhosis complications through metabolic stress, metabolism, and regeneration programs.
https://jobs.lever.co/ochre-bio/c8da319b-f300-4945-9a1d-1cfc97fc9c29
Post-doc Position in Dr. Marco Demaria’s Lab - ERIBA Labs, Groningen, Netherlands
https://www.linkedin.com/feed/update/urn:li:share:6963462684604252160
The Demaria lab are looking for a motivated postdoc to lead a project on chemotherapy-induced senescence.
Post-doc Position in David James’ and Mark Larance’s Lab - Charles Perkins Centre, University of Sydney, Australia
Interested in healthy ageing? David James and Mark Larance are looking for a motivated postdoc with experience in proteomics.
Please apply to David.james@sydney.edu.au
PhD Studentship in Dr. Ina Huppertz’s Lab - Max Planck Institute for Biology of Ageing, Cologne, Germany
https://www.ageing-grad-school.de/phd/host-lab-proposals/dr-ina-huppertz
Seeking a PhD student with a strong interest in RNA biology and metabolism.
Interview with Dr. Marco Demaria
Dr. Demaria gained his PhD in Molecular Medicine from the University of Torino, Italy where he researched the role of cellular metabolism and chronic inflammation on tumour progression. He then joined Prof. Judith Campisi's lab at the Buck Institute where he developed tools and methods to analyse senescent cells in vivo and made the important discovery of the role of transient cellular senescence in wound healing. He is now an Associate Professor at the ERIBA Labs and Group Leader of the Cellular Senescence and Age-Related Pathologies laboratory.
What inspired you to enter longevity research?
From a personal perspective, growing up living in close contact with my grandparents exposed me to the understanding of the ageing process very early in life. From a professional perspective, I began to do biomedical research on cancer. Looking for potential cancer drivers in the tumor microenvironment I encountered cellular senescence. I decided to join the laboratory of Judith Campisi to study it, and learned how senescence might be implicated in virtually every age-associated disease, not only cancer. This eventually inspired me to focus on the possibility that we might be able to target age-related mechanisms to extend quality of life and healthy longevity.
Which of the current theories of ageing do you think are the most convincing?
I have always been a supporter of antagonistic pleiotropy. I find it quite logical that evolution selected traits related to optimal fitness at young age without caring of the detriment that they could provoke in post-reproductive stages. I think the main topic of my research, cellular senescence, well fits that theory. While less convinced by the experimental evidence, I do not discard the idea of programmed aging. This is mainly driven by the fact that certain ageing mechanisms seem to follow a very regulated and reproducible trajectory.
How has the field changed since you started?
When I started in the field, pharmacological approaches to reduce age-associated features and to extend healthy longevity were very sporadic. Only when the hallmarks of aging started to become popularized, mainly thanks to the review in Cell in 2013, the pharma industry realized there were specific mechanisms to target. Also, more funding opportunities from public and private sources became available to researchers, thus boosting aging research. The field is exponentially growing, and we are just scratching the surface of understanding how ageing works. Exciting times.
What mistakes do you think the longevity field has made?
I think the longevity field has been too quick to move interventions forward, and there are too many parallel efforts in this direction with no standards and minimal exchange of knowledge. We risk to find that targeting individual hallmarks of ageing is only minimally impactful, and also to be unable to compare different studies. But making mistakes is not a problem if we learn something from them. In this case, a failure would direct towards a better standardization of how we read out ageing and towards development of combinatorial and synergistic approaches.
Other than your own, what do you think have been the biggest/important discoveries in the field?
Several discoveries from outstanding laboratories worldwide related to understanding basic mechanisms have been instrumental to improve our knowledge on how organisms age. In terms of therapeutic approaches, besides the concept that elimination of senescent cells can delay onset and progression of tissue dysfunctions, the idea that we can reprogram cells has been revolutionary for its potential in regenerative medicine.
What advice would you give to people currently working in longevity research?
First, try not to rush to conclusions. We are just starting to understand how various age-associated traits interact, and we should invest more resources for fundamental research in this area. Moving too quickly to interventions is risky and might jeopardize the current interest in the field. Second, let’s be more collaborative and collegial. I’m starting to see too many people pushing their ideas and not sharing with peers. Too many scientists talking about compound a and compound b without disclosing any detail. This can harm progress and knowledge.
Which aspect of longevity research do you think requires more attention?
As mentioned before, the formal description of the hallmarks of ageing popularized longevity research. However, this is an oversimplification. We should not think we have fully understood how ageing works, and we should invest more resources in doing basic science, not only in developing therapeutics. Finally, it is important to note that the current pharmacological approaches are mainly derived from what we are learning on the mechanisms engaged by good lifestyle choices – mainly diet and physical exercise. We need to think that these approaches might not work on individuals that are already taking good lifestyle choices. More attention should be taken in understanding what can further delay ageing on already long-lived organisms, and support more research in this area.
Is ageing a disease?
No, aging is a condition that increases our predisposition to develop diseases.
You have made significant advances to the field of cellular senescence. Could you summarise your discovery of the role that senescent cells play in wound healing and what the potential therapeutic implications could be?
Senescent cells are transiently induced during tissue damage and they promote optimal tissue repair. Currently, we know this phenomenon is happening in the heart, liver, kidney and skin but we think it might be an event occurring in every tissue. Because of this function, pro-senescence therapies, in particular interventions that can switch cell fate from death to senescence, can have an enormous potential to improve recovery from acute tissue injury and to avoid pathological sequelae.
There still lacks a universal marker for senescence – what do you think are the most robust markers discovered so far?
The three most senescence-associated markers remain activation of the lysosomal enzyme bgal, induction of the cell cycle inhibitor p16 and loss of the nuclear protein LaminB1. All these markers are not 100% specific, so combinations of them have the highest chance to reveal senescence in biospecimens. It is becoming more and more clear that different subtypes of senescent cells express subset-specific markers. Studies on senescence should start to incorporate such markers to identify the exact subpopulations.
Although senescence can be thought of as a tumour suppressor mechanism, research from you and others has highlighted the detrimental effect senescent cells can have. What do you think are the most promising senolytic strategies and what are the potential negative impacts of removing senescent cells?
There are several strategies to eliminate senescent cells, most of them leading to activation of apoptosis. Most of these approaches are based on re-purposed small molecules or natural compounds. The advantage is that they normally have a well-characterized safety profile in humans, and thus are more ready to enter clinical trials for a new indication. The disadvantage is that these compounds have senolytic properties but also additional senescence-independent on-target effects. This might lead to unwanted side effects and adverse reactions. Senolytics with increased targeted activity are under development, and promising results are shown by using senescence-specific peptides and gene therapy strategies. The potential negative impacts of targeting senescent cells might be reduced tumor immunosurveillance and impaired ability to repair acute tissue damages.
Outro
Thanks for your interest in the space and joining us yet again for VitaDAO’s Monthly Longevity Newsletter!
Don’t hesitate to contact us to let us know what you want to see next and give any feedback. We would love to hear from you! Until next time and if you’ve missed this month’s highlights, check this out on YouTube:
Further Reading
Cellular senescence in neuroinflammatory disease: new therapies for old cells?
https://www.cell.com/trends/molecular-medicine/fulltext/S1471-4914(22)00183-6
Age and life expectancy clocks based on machine learning analysis of mouse frailty
https://www.nature.com/articles/s41467-020-18446-0
Exercise as an Aging Mimetic: A New Perspective on the Mechanisms Behind Exercise as Preventive Medicine Against Age-Related Chronic Disease
https://www.frontiersin.org/articles/10.3389/fphys.2022.866792/full
Resistance Exercise Training as a Primary Countermeasure to Age-Related Chronic Disease
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6563593/
A distinct astrocyte subtype in the aging mouse brain characterized by impaired protein homeostasis
https://www.nature.com/articles/s43587-022-00257-1
Senescence-associated morphological profiles (SAMPs): an image-based phenotypic profiling method for evaluating the inter and intra model heterogeneity of senescence
https://www.aging-us.com/article/204072/text
New horizons in life extension, healthspan extension and exceptional longevity
https://academic.oup.com/ageing/article/51/8/afac156/6653481?login=true
Transformed cells after senescence give rise to more severe tumor phenotypes than transformed non-senescent cells
https://www.sciencedirect.com/science/article/pii/S0304383522003342?via%3Dihub
Somatic mutations in single human cardiomyocytes reveal age-associated DNA damage and widespread oxidative genotoxicity
https://www.nature.com/articles/s43587-022-00261-5
Plasma proteome profiling of healthy individuals across the life span in a Sicilian cohort with long-lived individuals
https://onlinelibrary.wiley.com/doi/10.1111/acel.13684
Living in endemic area for infectious diseases accelerates epigenetic age
https://www.sciencedirect.com/science/article/pii/S0047637422000951
Metabolic changes in aging humans: current evidence and therapeutic strategies
https://www.jci.org/articles/view/158451
Developmentally-programmed cellular senescence is conserved and widespread in zebrafish
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7585104/
Autophagy-nutrient sensing pathways in diabetic complications
https://www.sciencedirect.com/science/article/abs/pii/S104366182200353X?via%3Dihub
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