Welcome back to VitaDAO’s monthly longevity research newsletter — we hope you enjoyed our maiden issue!
The longevity field remains one of the most controversial areas of science. There are a number of common objections which arise to the concept of trying to understand ageing and increasing lifespan, such as: overpopulation, wealth inequality, long-lived dictators, slower progress, longer decrepitude, unsustainable pensions, being against the “natural order” and many others. For a great discussion of all these points with interesting counter-arguments, check out: https://agingbiotech.info/objections/.
Another problem is that the field has often been infiltrated with quacks, snake oil and sensationalist headlines — often claiming to have discovered the “elixir of life” or the “fountain of youth”. Sadly, this issue will only get exacerbated as interest in ageing research grows and gains more popularity in the public eye. As longevity gets more “trendy” and becomes more of a buzzword even greater caution must be taken with anti-aging pills salesmen.
It is therefore important that the longevity space doesn’t become an echo chamber, but rather an open and transparent community which welcomes intellectual discourse. That’s why this month we reached out to Prof. Charles Brenner, a prolific critic of numerous ideas within the longevity field, for his take on things. He kindly provided us with some important words of caution as well as interesting thoughts on the inextricable link between development and ageing. Prof. Brenner also participated in a no-holds-barred debate with Prof. Aubrey de Grey (on the Let’s Talk Longevity Podcast — featured below) on the idea of Longevity Escape Velocity and how near/realistic it is.
At VitaDAO we are devoted to supporting projects with strong scientific integrity which aim to tackle age-related diseases with the hope of increasing healthspan and genuinely improving peoples’ lives.
VitaDAO-funded Research Projects
This month VitaDAO has funded a 4 year doctoral research program to probe DNA quadruplexes in age-related proteostasis
Prof. Tim Peterson has been awarded 231,000 USD to design new drugs to build upon chemistry which he discovered can act as a “cellular soap” to simultaneously target both pathogens and senescent cells:
Longevity Literature Hot Picks
Once again, the abundance of great longevity research that was published this month has been hard to keep up with, but here are some of our favourite papers to keep you up-to-date with the field.
Young CSF restores oligodendrogenesis and memory in aged mice via Fgf17
https://www.nature.com/articles/s41586-022-04722-0
Infusing cerebrospinal fluid from young mice into the brains of aged mice was shown to boost oligodendrocyte progenitor cell (OPC) proliferation and differentiation in the aged hippocampus and improve memory. They identified fibroblast growth factor 17 (Fgf17) as a protein in the young serum which confers these beneficial effects by activating the transcription factor — serum response factor (SRF).
Senescence-induced endothelial phenotypes underpin immune-mediated senescence surveillance
http://genesdev.cshlp.org/content/early/2022/05/25/gad.349585.122.long
Senescence surveillance mechanisms allow for the recruitment of immune cells to specifically remove senescent cells. Here the authors show that senescent cells induce local endothelium to become an organising centre for the adaptive immune response during senescence surveillance.
Circadian alignment of early onset caloric restriction promotes longevity in male C57BL/6J mice
https://www.science.org/doi/10.1126/science.abk0297
Caloric restriction has been observed to increase healthspan/lifespan in a number of model organisms. However, trying to unravel the relative contribution of calorie reduction versus fasting proves difficult as calorie restricted animals tend to consume their food quicker and thus spend a longer time fasting. Here the authors show that calorie restriction increases lifespan more when there is a fasting period of 12 hours as opposed to feeding regularly throughout the day. They also observed a further increase in lifespan if the food was restricted to the time corresponding to the active phase of their circadian rhythm, although further research is required to determine if this difference is due to altered sleeping patterns in mice from the opposing feeding schedule.
Calorie restriction and calorie dilution have different impacts on body fat, metabolism, behavior, and hypothalamic gene expression
https://www.cell.com/cell-reports/fulltext/S2211-1247(22)00608-8
Another consideration to understanding the role of diet on lifespan is discerning the relative effects that the food content itself versus the process of ingestion has on the ageing process. Here the authors compare calorie restriction to calorie dilution (ad lib diet with indigestible components) and find that hunger signalling is a key process mediating the benefits of CR.
Dietary intervention improves health metrics and life expectancy of the genetically obese Titan mouse
https://www.nature.com/articles/s42003-022-03339-3
The Titan mouse line has previously been thought of as a model for healthy obesity, but here it is shown that they have numerous metabolic dysfunctions and are short lived. However, switching to a energy-reduced feed was able to restore some of these dysfunctions and significantly increase their lifespan.
The importance of aging in cancer research
https://www.nature.com/articles/s43587-022-00231-x
An interesting editorial highlighting that although cancer is generally an age-associated disease, most animal research is performed in relatively young animals and in human clinical trials, patients over the age of 75 years old are under-represented.
Fecal microbiota transfer between young and aged mice reverses hallmarks of the aging gut, eye, and brain
https://microbiomejournal.biomedcentral.com/articles/10.1186/s40168-022-01243-w
Fecal microbiota transplants, or stool transplants, have been gaining traction in recent years. In this paper, the authors show that transplanting intestinal microbiota from old to young mice can result in an acceleration of both age-associated central nervous system and retinal inflammation, whereas transplanting microbiota from young to old can attenuate these effects.
The relationship between epigenetic age and the hallmarks of ageing in human cells
https://www.nature.com/articles/s43587-022-00220-0
Epigenetic clock scores have been linked to several age-related processes and have shown accuracy as mortality predictors, however further research has been needed to understand the underlying mechanisms. Here the authors show that epigenetic ageing is associated with stem cell composition, mitochondrial activity and nutrient sensing, however independent from genomic instability, telomere attrition and cellular senescence.
Clinical Trial Updates
Curcumin and Function in Older Adults (SPICE)
Resveratrol and Exercise to Treat Functional Limitations in Late Life
Dementia Risk and Dynamic Response to Exercise (DYNAMIC)
News
Oviva announces $11.5M in Seed Financing to improve ovarian health and extend female healthspan through therapeutic innovation
Upcoming conferences
4th Annual Longevity Therapeutics Summit
28–30th June 2022, San Francisco, USA
https://longevity-therapeutics.com/
5th International Symposium on Neurobiology & Neuroendocrinology of Aging
15–19th July 2022, Bergenz, Austria
http://www.neurobiology-and-neuroendocrinology-of-aging.org/
5th Annual Ending Age-Related Diseases Conference
11–14th August 2022, virtual meeting
https://www.lifespan.io/ending-age-related-diseases-2022/
9th Aging Research and Drug Discovery Meeting (ARDD)
29th August — 2nd September 2022, Copenhagen, Denmark
Funding Opportunities
Merck Grants to Stimulate Innovative Research
Drug discovery — 3 grants comprising up to 500,000 €/year for 3 years with the option of extension for applicants with an interest in approaches interfering with the molecular hallmarks of ageing to promote healthy longevity.
https://www.merckgroup.com/en/research/open-innovation/research-grants.html
The San Diego Nathan Shock Center (SD-NSC) Pilot Grant program
Seeking projects that explore the heterogeneity of aging.
Proposals are due by August 24 2022.
https://www.salk.edu/science/research-centers/san-diego-nathan-shock-center/pilot-grant-program/
Job board
Open Research Assistant position in Manning Lab — Harvard University, US
https://www.hsph.harvard.edu/molecular-metabolism/academic-position-openings/
To explore how the PI3K-mTOR signaling network is altered in cancer, diabetes, and aging, and how targeting components of the signaling network might lead to new insights into how to treat or prevent these conditions
Post-doc position available in Alan Attie’s Lab — University of Wisconsin-Madison, US
To work on transcription factors that affect beta-cell function and diabetes susceptibility — learning genetics/genomics and beta-cell biology. Apply to: adattie@wisc.edu
PhD Studentship in Kristina Kirschner’s Lab — Beatson Institute, University of Glasgow, UK
Working on senescence heterogeneity and liver cancer
https://www.beatson.gla.ac.uk/Education/Studentships/
Senior Post-doc position in Gavin Richardson’s Lab — Newcastle University, UK
To investigate senescence and cardiovascular disease.
https://jobs.ncl.ac.uk/job/Newcastle-Research-Associate/795078901/
Five Group Leaders Positions — University of Coimbra, Portugal
The Multidisciplinary Institute of Ageing will soon be opening for applications for group leader positions in the biology of ageing. Watch this space: www.uc.pt/mia
Postdoctoral and technician positions in the Lamming Lab — University of Wisconsin-Madison, US
To investigate how what, when, and how much we eat regulates healthy aging using mouse models: https://lamminglab.medicine.wisc.edu
Head of Engineering (co-founder), Head of Biosimulation (co-founder), Product Manager, CTO, Backend, Frontend, Scientific Developer and multiple other roles at Formic Labs: https://apply.workable.com/formic-labs/
Formic Labs is building an AWS-inspired platform for life sciences R&D that alleviates many of the bottlenecks to integrating knowledge.
Bioinformatician — Teal Omics
Teal Omics is an aging company with a mission to transform healthcare by developing a deep, personalized, and data-driven understanding of age-related diseases, based on research by the Wyss-Coray lab at Stanford University. Contact: alex@tealomics.com
Lab tech or early career scientist — Vincere, Boston, MA, US
https://www.indeed.com/cmp/Vincere-Biosciences,-Inc/
Vincere runs cell culture assays related to mitochondrial pathways. Experience with cell culture is a must, and experience with mitochondrial readouts would be a plus.
Debate: Aubrey de Grey vs Charles Brenner — Longevity Escape Velocity
The gloves were off in this eagerly anticipated debate between Aubrey de Grey and Charles Brenner, on the topic of how realistic/near we are from longevity escape velocity (LEV) — the idea that if the rate of lifespan expansion from medical advancements outpaces the actual passage of time, that we would achieve biological immortality. Just in case you had any doubts about which of the debaters thought we are nearing LEV, here are a few snippets to whet your appetite:
Brenner: “You don’t have any evidence that if you can remove these types of damage that any animal with longer”
DeGrey: “I’m saying we have a 50:50 chance of reaching longevity escape velocity in 15 years from now”……………”
Brenner: “and I’m saying you don’t”
Brenner: “You don’t consider this fantastical?”
Brenner: “Your approaches are so naive”
Check it out here:
S01 E01 — On Longevity Escape Velocity with Aubrey de Grey & Charles Brenner
https://rss.com/podcasts/letstalklongevity/480365/
Interview with Charles Brenner
Charles Brenner received his PhD from Stanford University and has made several important contributions to biochemistry and molecular biology — including the discovery of nicotinamide riboside (NR) as a nicotinamide adenine dinucleotide (NAD) precursor vitamin. He is currently a professor and department chair at City of Hope and also known for his public criticism of many aspects within the ageing field.
Ageing rates and lifespans vary hugely within the animal kingdom — what are your thoughts on trying to understand the mechanisms underlying these differences in hope of translating this knowledge to increasing human healthspan/lifespan?
Different animals reach reproductive maturity at different rates. In large part, animals that take a long time to reach reproductive maturity are longer lived. For sure, there’s discoverable knowledge in the rates of animal development.
Which of the current theories of ageing do you think are the most convincing?
To my mind, aging starts at fertilization and is inextricably linked to development. The fact that the most powerful monogenic longevity genes are loss of function alleles of genes conserved for growth is telling us a powerful lesson. In fact, they are not conserved as longevity genes because their normal functions, which are also essential for reproduction, are growth. It’s also quite evident that all vertebrates exhibit a loss of repair capacity after they are reproductively mature. I don’t have much use for terms like the information theory of aging or the seven types of damage that constitute aging.
Do you think trying to understand the mechanisms driving ageing, with a view to targeting all age-related diseases simultaneously, is a viable parallel strategy to researching these diseases individually? And do you have concerns about the scientific rigour about current attempts at this approach?
I find it astonishing that some investors and newcomers have been brought into this field who have been swayed into thinking that aging is a simply correctible engineering flaw and not a basic part of everyone’s life course. If it weren’t for aging, a fertilized egg could not develop into a born animal, and there would be no growth, puberty or maturation. The most powerful genes ever found that control aging are involved in all of these processes.
If the goal is to help more people lead healthier lives, I’m all for that. The pitch is usually much more extravagant though.
I’m not going to make a blanket critique of approaches but I have been quoted as saying that the SENS approach is structurally unsuitable to make significant progress; in vivo reprogramming is going to be much harder that some people made it out to be; and CRISPR doesn’t change very much because there isn’t a dominantly acting longevity gene that everyone needs more copies of.
Do you think ageing is treatable?
You mean do I think that we can prevent post-reproductive decline or do I think we can age better? I think we can age better. I don’t think that we can prevent post-reproductive decline but it is surely possible to stay in good form for a long time.
What do you think is the most promising longevity intervention?
High physical and mental activity is the single most important intervention. There’s nothing even close to that.
If a prophylactic drug were shown to delay the onset of numerous/all age-related diseases — would you support this? And how would you define/characterise this in terms of FDA disease indications?
Sure, why not? I’m sure you know that it would have to be approved for a disease or condition. If its mechanism of action were such that it delays the onset of other diseases, it would likely be used off label. This is already the case for drugs that have not been shown to delay the onset of age-related conditions in healthy older people. Here I’m referring to rapamycin and metformin.
I also do not think there’s a nefarious plot of biotech or pharma to not develop anti-aging drugs. I think the incentives are already present in our system for people to discover and test important new molecules and for the most part, drugs are approved when the safety and efficacy data support their approval.
What do you think have been the biggest/important discoveries in the field?
I think more people should read the work of Michael Rose on the polygenic nature of longevity and the fact that longevity has generally not been under selective pressure in animals. It is out of this work, that I realized that longevity is an emergent property of other key measures of fitness such as the ability to obtain food, avoid predation, attract a mate, reproduce and take care of young ones. Animal gene sets can then move toward longevity when mothers and fathers are able to reproduce multiple times but it’s not like there is a magical dominantly acting longevity gene. It’s more like nearly every gene has to promote the function of all the organs to do all the things over time.
What are your thoughts on the concept of “biological age” and what do you think the most accurate way to determine this is?
There’s something to it but the kits have zero value to consumers. Subjectively, I agree with the statement “you’re as young as you feel” and in the context of something like dating or running a mile, a 30, 40, 50, 60 or 70 year old person can perform more or less youthfully than their chronological age.
There are also DNA methylation marks that track aging and have some value in predicting future mortality. But we’ve recently read that the GrimAge score goes up during infection and then goes down as the infection is resolved, so I have a concern that some of what is being measured is inflammation. The whole biological age program is a research project to obtain biomarkers that could potentially be used in interventional trials. But while you are trying to figure out if a lower GrimAge score, for example, means that a person is healthier and you don’t yet know that, you can’t score the result of an intervention simply based on their GrimAge score going down. I have publicly stated that we know enough about growth hormone to consider it a pro-aging intervention such that for GrimAge to go down in the TRIIM trial suggests that GrimAge is not measuring what we think it is measuring.
What mistakes do you think the longevity field has made?
Oh gosh, where to begin? Longevity has been a non-evidence based and unfulfillable promise since time immemorial full of potions, vacation spots, magic pills and requests for funding.
Although there is real science to aging, there are individuals in the field who represent themselves as scientists, who are really just promoters. They are actually pretty easy to spot because their ideas are not falsifiable. Their talks, books and appearances do not teach critical thinking. Instead, they are longevity gurus who convince people that they have found the path. These individuals have outsized influence particularly in public spheres, which has seriously damaged the field and I categorically reject the notion that they have helped the field by bringing in money. The consumers and investors attracted by gurus are being damaged and the field of aging science is damaged by hypesters. Hype hurts.
What would you do differently to the approaches currently taken? / What changes would you like to see within the field?
I’m pretty clear that we have to shun longevity gurus. We need to realize we are living in the real world in which we haven’t identified dominantly acting longevity genes, Yamanaka factors are oncogenic and teratogenic, and our gene set has been selected for us to reproduce and provide care to our offspring but has never been under selective pressure to maintain our fitness into a tenth decade. I plan to test some approaches to support repair capacity as we age — I think that NR may have activity in this respect.
What advice would you give to people currently working in longevity research?
Learn and respect developmental biology. Make sure that lab staff are blinded to treatment. Learn from people with falsifiable hypotheses. Steer clear from influencers and promotional review articles.
Outro
Thanks for reading our second issue of VitaDAO’s Monthly Longevity Newsletter!
Once again, if there is anything you would like us to feature in future issues, please get in contact.
Next month we will be highlighting some of the prominent theories of ageing and featuring an interview with Professor Emeritus Thomas Kirkwood — formulator of the Disposable Soma Theory of Ageing — not to be missed!
If you are keen to see what else has been going on in the VitaDAO community, we have provided links below to some of our highlights from the past month — enjoy and we look forward to seeing you next month!
Subscribe here for more!
The Science of Biostasis and Cryopreservation with Kai Micah Mills & Dr. Emil Kendziorra
https://www.youtube.com/watch?v=X9mH1punHx4
Applied Longevity Medicine with Prof. Evelyne Bischof, Prof. Andrea B. Maier and Weronika Prusisz
https://www.youtube.com/watch?v=uGvF3Q-IJf0
Pay for success x IP NFT Pilot — A New Financial Model for Repurposing Off Patent Rapamycin
https://www.youtube.com/watch?v=1j4zMH-4vqE
Bridging IP into Web3 with IP-NFTs
https://www.youtube.com/watch?v=TjUuC9lL_i4
Crypto Meets Longevity with Qiao Wang
https://www.youtube.com/watch?v=BhHeBCM1lbU
Decentralising Healthcare through Geroscience with Prof. Brian Kennedy
https://www.youtube.com/watch?v=VHlKFXJ-lgA
Last but not least, we invite you to watch the full recording of DeSci.Berlin I Advancing Scientific Collaboration, or find the individual talks of some incredible speakers at Molecule’s YouTube channel
https://www.youtube.com/watch?v=sMgNQakX0QA&t=10449s
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