Longevity Research Newsletter July 2022

Why do we age? Is aging a result of a genetic program encoded within each of our cells, or is it simply a consequence of damage accumulation throughout life? Do we stand a chance in intervening or is it futile and physically impossible to stop the ever increasing entropy? Many theories of aging have been proposed which aim to answer these questions.

One side of the story is the accumulation of damage. This can take many forms. From the wear and tear hypothesis to accumulation of DNA mutations, free radicals, protein crosslinks or aggregates. The other side suggests there are programs in place to regulate cell life and turnover. This could include anything from telomeres getting shorter with each cell division, to cellular senescence perturbing tissue homeostasis and driving inflammation, to your favourite longevity gene, that if altered might impact on lifespan.

This is of course not an exhaustive list. You can see our previous issue for Charles Brenner’s take on why ageing is inextricably linked to development and how a decline in repair capacity is a major contributor to aging. And of course the highlight of this month’s newsletter is our interview with Professor Tom Kirkwood, who formulated the disposable soma theory of aging, which addresses evolutionary trade-offs between investment in reproduction vs maintenance of our somatic cells.

VitaDAO-funded Research Projects

The VitaDAO community have voted, with a 71.22% majority, to fund Repair Biotechnologies - a preclinical-stage biotech company developing a first-in-class universal cell therapy for atherosclerosis (the main cause of cardiovascular disease). The aim will be to engineer macrophages, to express a protein capable of degrading excess cholesterol, which can then be delivered to patients.

https://snapshot.org/#/vote.vitadao.eth/proposal/0x843c0e546ecfdcfb850ba00e88bcfd8c4a1e9204f838342dbbf98a81606a50f6

Longevity Literature Hot Picks

While we’re on the topic of theories of aging, we need to mention last month’s hot pick, which contributes to the discussion.

The relationship between epigenetic age and the hallmarks of ageing in human cells https://www.nature.com/articles/s43587-022-00220-0

The paper bridges together the deterministic epigenetically programmed aging theory and the stochastic “wear and tear” one. Multiple mechanisms are playing out synchronously but independently as seen by the disconnect between the hallmarks of aging and epigenetic clocks. More on this in our previous issue and now back to this month’s picks hot off the press.

Diverse partial reprogramming strategies restore youthful gene expression and transiently suppress cell identity

https://www.sciencedirect.com/science/article/abs/pii/S240547122200223X

Partial reprogramming restored youthful expression in two cell types - adipogenic and mesenchymal stem cells, but it also suppressed somatic identity programs temporarily, as demonstrated by single cell genomics. The study tests multiple subsets and combinations of Yamanaka factors and compares how they restore youthful expression and to what degree they suppress somatic identity.

Lipid metabolism dysfunction induced by age-dependent DNA methylation accelerates aging

https://www.nature.com/articles/s41392-022-00964-6

The changes in the epigenome and cell metabolism interact and contribute to aging. The Elovl2 gene is found to correlate strongly with age and it’s involved in lipid metabolism regulation. If its function is impaired an aging phenotype occurs due to endoplasmic reticulum stress and mitochondrial dysfunction.

Dietary restriction and the transcription factor clock delay eye aging to extend lifespan in Drosophila Melanogaster

https://www.nature.com/articles/s41467-022-30975-4

Visual senescence and altered light perception can negatively affect the circadian rhythm which is associated with decreased lifespan. Dietary restriction reduced the photoreceptor activation, thus amplifying circadian rhythm and mitigated the shortened lifespan phenotype.

Measuring biological age using omics data

https://www.nature.com/articles/s41576-022-00511-7

The review pulls together recent advancements in high-throughput omics and how the data can be used to build reliable aging clocks by harvesting the power of machine learning. This can not only integrate the information from the epigenome, transcriptome, proteome and metabolome but it has also shown the capability to identify novel aging biomarkers.

Molecular mechanisms of exceptional lifespan increase of Drosophila melanogaster with different genotypes after combinations of pro-longevity interventions

https://www.nature.com/articles/s42003-022-03524-4

The combination of multiple pro-longevity strategies indeed lengthens Drosophila lifespan by impacting epigenetics, nutrient sensing, autophagy, immune response, lipid metabolism and cellular respiration. There was a trade off of locomotion for longevity in the flies.

Skin Aging in Long-Lived Naked Mole-Rats is Accompanied by Increased Expression of Longevity-Associated and Tumor Suppressor Genes

https://www.sciencedirect.com/science/article/pii/S0022202X2200402X

While there are a number of similarities between human and naked mole rat (NMR) skin aging such as decrease of epidermal thickness, keratinocyte proliferation, and a decline in the number of Merkel cells, T-cells, and expression levels of dermal collagens, there are some contrasts in the expression of certain longevity-related and tumour-suppressor genes in NMR skin that likely protect it from damage and skin cancer.

Inference of age-associated transcription factor regulatory activity changes in single cells

https://www.nature.com/articles/s43587-022-00233-9

Transcription factors (TFs) are vital for cell function and cell differentiation, which is why it is important to understand their role in the aging process. This study reveals age-associated macrophage dedifferentiation across tissues, with a single cell resolution.

Comparative transcriptomics reveals circadian and pluripotency networks as two pillars of longevity regulation

https://www.sciencedirect.com/science/article/pii/S1550413122001383

Transcriptomic analysis of 26 diverse mammalian species with varying lifespans shows that genes for inflammation and energy metabolism are associated with lower lifespans compared to expression of genes for RNA transport, microtubule organisation and DNA repair correlate with longer lifespans.

Autophagy at the intersection of aging, senescence, and cancer

https://febs.onlinelibrary.wiley.com/doi/10.1002/1878-0261.13269

An interesting review from Narita lab discussing the roles of autophagy in the maintenance of stem cell populations and prevention of cellular senescence, along with how stress-induced senescence might rely upon autophagy. They also describe evidence suggesting autophagy can have a tumour suppressive or promoting effects in early vs late stage tumorigenesis respectively.

The Less We Eat, the Longer We Live: Can Caloric Restriction Help Us Become Centenarians?

https://www.mdpi.com/1422-0067/23/12/6546/htm

Calorie restriction is one of the most studied interventions in longevity research - here the authors review the literature on the metabolic pathways involved and potential for lifespan extension in humans.

And last but not least, an exciting pre-print from Calico:

The complete cell atlas of an aging multicellular organism https://www.biorxiv.org/content/10.1101/2022.06.15.496201v1

Aging in C. elegans is described to be a tightly coordinated process involving mostly metabolic and stress-response genes. The signatures of aging in different cell types were distinctly different with one common factor of decreased energy metabolism.

Clinical Trial Updates

A small clinical trial for rectal cancer observes remission in 100% of patients!

https://www.nejm.org/doi/full/10.1056/NEJMoa2201445

Administering the monoclonal antibody Dostarlimab, an inhibitor of programmed death 1 (PD-1), to patients with a subset of rectal cancer characterised by a DNA mismatch repair deficiency was able to clear all observable cancer in every patient.

News

Saudi Arabia plans to spend $1 billion a year discovering treatments to slow aging

https://www.technologyreview.com/2022/06/07/1053132/saudi-arabia-slow-aging-metformin/

The Hevolution Foundation’s mission is to make ageing healthier by supporting innovation in life sciences and medicine with grants and investments that focus on targeting the biology of ageing itself, rather than specific diseases.

Insilico raise $60M in Series D funding

https://endpts.com/no-humans-allowed-alex-zhavoronkov-adds-robotic-lab-to-his-ai-drug-discovery-play-as-insilico-unveils-60m-raise/

Upcoming conferences

Ending Age Related Diseases

August 11-14th, virtual

https://www.lifespan.io/ending-age-related-diseases-2022/

9th Aging Research and Drug Discovery (ARDD) Meeting

August 29th - September 2nd, Copenhagen

http://www.agingpharma.org/

Longevity Summit Dublin 2022

September 18th-20th, Dublin

https://longevitysummitdublin.com/

Job board

Lab technician or early career scientist at Vincere

https://www.indeed.com/cmp/Vincere-Biosciences,-Inc/

Vincere is working to slow or stop Parkinson's and other age-related diseases. They are hiring a lab tech or early career scientist to work at the bench in Boston, MA running cell culture assays related to mitochondrial pathways.

Postdoctoral fellowships at University of New Mexico School of Medicine, U.S

https://hsc.unm.edu/medicine/education/reo/training-programs/asert/

The McCormick Lab - working on delaying ageing - are an eligible lab for this call and are welcoming people to get in contact!

Postdoctoral Research Fellow in Dr. Adam Antebi’s Lab - Max Planck Institute for Biology of Ageing, Cologne, Germany

https://www.age.mpg.de/career-education/open-positions

A great opportunity for a post-doc who has expertise in fish biology to work on a project to understand ageing in killifish.

Interview with Professor Thomas Kirkwood

Prof. Tom Kirkwood received his PhD from Cambridge University and went on to have a prolific career in gerontology research. Most notably, he formulated the “disposable soma theory of ageing”. Prof. Kirkwood has also made great contributions to the promotion of ageing research, including publishing the popular science books “Time of Our Lives” and “The End of Age: Why Everything About Aging Is Changing”. He was appointed Commander of the Order of the British Empire (CBE) in the 2009 New Year Honours.

What inspired you to enter longevity research?

A mixture of chance and curiosity. I was working on something totally different when a colleague, the distinguished molecular geneticist Robin Holliday, happened to ask for my thoughts on a question concerning replicative senescence. It sounded interesting, we began a productive collaboration, and my curiosity just grew and grew.

How has the field changed since you started?

The field was tiny when I started in the mid-1970s. People had speculated about ageing for a very long time, but labs dedicated to longevity research were then very rare. It would be several years before I got a job that actually included my work on ageing, but I was lucky that my growing interest was tolerated by my then employer. Today, the extent of the network of longevity labs is amazing.

Other than your own, what do you think have been the biggest/important discoveries in the field?

The discovery of replicative senescence in the 1960s was a milestone, though it took many years to reach our present understanding. So many big discoveries have been made about molecular and cellular aspects of ageing and longevity. Among the biggest are the role of signalling pathways, genetics and epigenetics, and the significance of a systems approach.

What advice would you give to people currently working in longevity research?

Enjoy the challenge – this is an exciting time to be in the field. Ageing is complex – respect the complexity. A Nobel Prize-winning physicist once said “one should neither seek nor avoid complexity in addressing the problem at hand”. I’ve found this advice very helpful. Make time to read and think widely. Unexpected connections can arise that lead to breakthroughs.

Which aspect of longevity research do you think requires more attention?

Addressing complexity via systems approaches is certainly one. Ageing plays out via multiple mechanisms at multiple levels. Personally I’m very keen on using the power of evolutionary analysis to connect the big Why? and How? questions. Also, a striking feature of ageing is its inherent variability – this needs some more serious attention.

Is ageing a disease?

For me, ageing isn’t a disease in the sense I would usually apply to this term. It’s a normal process. But by its very nature it involves the generation of molecular and cellular abnormality. This feeds into multiple kinds of dysfunction. When a particular kind of dysfunction – which may have causes additional to ageing – passes a threshold recognised by clinicians, it gets a diagnosis of disease.

You are most well-known for proposing the Disposable Soma Theory of Ageing? Could you summarise this in a couple of sentences?

The disposable soma theory (DST) proposes an answer to the question: how much of its energy should an organism invest in the long-term maintenance of its somatic tissues? The answer is that, whereas it is important for the germ-line to be immortal, the soma needs only to be maintained well enough to remain in sound condition for as long as the individual might reasonably expect to still be alive. In nature, most deaths result from external risks, so the deleterious consequences of limited maintenance don’t count much in the evolutionary struggle for survival.

How well do you think the disposable soma theory has aged?

The essential predictions of DST are (i) somatic cells should be less well protected than germ cells, and (ii) species longevity should be regulated by selection to raise or lower the level of somatic maintenance in relation to the hazard rates in the species’ ecological niche. Both of these predictions are very well supported.

There are interesting questions about how the resources freed up by limiting the investment in maintenance should be invested to maximise Darwinian fitness, for example, by enhancing reproduction and/or growth rate. In other words, should we see trade-offs between longevity and reproduction (or other life history traits)? Much evidence supports the existence of such trade-offs, but exceptions have been found. These, together with growing data on the diversity of ageing across the tree of life, have prompted some interesting developments. These are important for our understanding of longevity science but the DST has the flexibility to accommodate them. So to answer the question, I think the DST has aged well. Like all of us, it’s been challenged by new experience and become older and wiser along the way.

Are there any criticisms (such as women being longer lived compared to men, or longevity benefits of caloric restriction) which you think hold merit / are there amendments you would make to the theory now?

Critical challenge of a theory is always welcome, but neither of these is a serious problem.

Regarding sex differences, females in many species make more direct investments in reproduction than males, so it might seem strange that they are appear also to be better maintained. But, one must not overlook the big investments made by males in reproductive competition, which can be very costly. Since the integrity of the female soma is essential to nurture the next generation, it might indeed be less disposable than the male soma.

Regarding CR, how can less nutrition cause longer lives? One suggestion, made by others, is that famine may cause an animal to suspend reproduction, which might allow maintenance to be temporarily boosted to preserve integrity for when the famine is over. We have shown this to be at least theoretically possible, but other possibilities exist. The DST provides a framework within such questions can be considered, but they don’t constitute critical predictions of the theory.

The DST framework, based as it is on the principle of evolutionary optimisation of resource allocation strategies, has relevance for very diverse organisms, as others as well as I have recognised. These extend well beyond the case originally in mind of a multicellular animal with a strict distinction between germline and soma. In this sense, the theory offers exciting opportunities for further adaptation or amendment.

Outro

Thanks for sticking with us for another issue of VitaDAO’s Monthly Longevity Newsletter!

As always, we would love to hear your feedback and suggestions for content you want to see. For now we will leave you with our highlights for the past month and we hope to see you again for our next issue!

Meet The Vitalians | Imagining the future of VitaDAO | With Tim Peterson

https://www.youtube.com/watch?v=O2xZZR1sydA

VitaDAO IP-NFT Transfer Ceremony with Molecule & Evandro Fang

https://www.youtube.com/watch?v=ZcUXGzgm8_k

MenoAGE - Community Call

https://www.youtube.com/watch?v=KH2qRMm-QY0

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