Aging Research and Drug Discovery Meeting

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Aging Research and Drug Discovery Meeting
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Last week I attended the 9th Aging Research and Drug Discovery Meeting (August 29 – September 2, 2022), a conference bringing together representatives from the pharmaceutical industry, startups, and academia. Begun in 2014 as an EBMO conference forum, ARDD was established as an independent meeting three years ago. It now typically welcomes roughly 2,000 attendees, this year both virtually (as in my case) and in-person at the University of Copenhagen. This year, over 100 speakers, about two thirds of them from universities and research institutes, discussed the latest findings on the molecular, cellular, and organismal bases of ageing and on the development of preventions and treatments. The discussion is a timely one: according to the UN, people aged 65 and over have outnumbered children under five since 2018, and the global proportion of people over the age of 80 is projected to triple from 2019 levels by 2050. Some highlights of the conference are summarized below.

Longevity medicine

 The meeting kicked off with two workshops, one on emerging technology (e.g., blockchain, AI) and the other on longevity medicine. The latter, co-organized by Springer Nature’s own Sebastien Thuault, Chief Editor of Nature Ageing, highlighted a growing field of medical research aimed at extending both lifespan and healthspan.

A major challenge facing the field of longevity medicine is the diffuse nature of the target, as ageing encompasses a wide range of mechanisms and effects. Dr. Nir Barzilai (Albert Einstein College of Medicine, USA) outlined an ambitious plan to address this challenge by treating ageing itself rather than treating each age-related condition separately. Through a multi-centre series of clinical trials known as the TAME (Targeting Aging with Metformin) Trial, Dr. Barzilai and colleagues hope to show that Metformin, a standard treatment for type 2 diabetes that delays ageing in animals, can also slow the progression of age-related diseases like cancer, heart disease, and dementia in humans. If successful, the TAME Trial may prompt the FDA to recognize ageing as a treatable indication, laying the groundwork for the “gerotherapeutical” repurposing of other FDA-approved drugs such as rapamycin, ACE inhibitors, and even aspirin.

Inflammaging and immunosenescence

A frequent theme of the meeting was the effect of ageing on the immune system and how to mitigate it. Immunosenescence, or the deterioration of the immune system, is exacerbated by inflammaging, or the chronic, low-grade systemic inflammation that comes with age. For example, the thymus shows accelerated ageing relative to other organs, beginning to shrink in humans after puberty; by middle age, naïve T cell output is much reduced and the primary constituent of the thymic space is ectopic lipids. Dr. Vishwa Dixit (Yale School of Medicine) described how this immunosenescence was reversed after two years of moderate (15%) caloric restriction in CALERIE-II (Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy) study participants. Thymic rejuvenation was accompanied by decreased adipose tissue expression of platelet-activating factor acetylhydrolase (PLA2G7), a key regulator of immunometabolic pathways, and of SPARC, an adipokine that promotes a pro-inflammatory phenotype in adipose macrophages. Dr. Dixit’s results suggest that blocking SPARC production pharmaceutically may mimic the beneficial effects of caloric restriction without the challenges of long-term dieting.

Similarly, Dr. Stuart Cook (Duke-NUS Medical School, Singapore) discussed how interleukin 11, a pro-inflammatory, anti-regenerative cytokine, may be targeted to slow the ageing process. Using a range of primary human cell types and genetically and pharmacologically manipulated mice, Dr. Cook demonstrated that IL11 is an upstream inhibitor of the tumor suppressor LKB1, whose inhibition in turn prompts activation of mTOR and of downstream factors that promote ageing. Mice with IL11 receptor knockout or that were treated with anti-ILL antibodies showed reductions in age-related thymus and brain atrophy, liver stenosis and fibrosis, and frailty. While targeting each of the factors in this IL11-controlled pathway individually, e.g., with metformin, rapamycin, and senolytics, can lead to on-target toxicity, targeting IL11 directly may affect only ageing-related pathways. 

Mitochondrial effects: beyond reactive oxygen species

Mitochondria are a usual suspect at ageing meetings, often in the context of the mitochondrial theory of ageing. According to this theory, accumulating mutations in mtDNA drive a vicious cycle of respiratory chain dysfunction, free radical production, and further mtDNA mutations. The theory was supported nearly two decades ago by a model of premature ageing known as the mtDNA mutator mouse, which produces a proofreading-deficient version of mitochondrial DNA polymerase. Yet, mtDNA mutations in other mouse models and in human patients do not show accelerated ageing, casting doubt on the theory and raising questions about the mechanism underling the mtDNA mutator phenotype. In addressing these questions, Dr. Anu Suomalainen (University of Helsinki) and colleagues recently discovered that the mtDNA of these mutator mice is characterized by increased rates not only of mutation but also of replication. The resulting sequestration of dNTPS in the mitochondria leads to depleted nuclear pools, causing stalled nuclear DNA replication fork progression, chronic DNA replication stress, impeded cell cycling, and premature ageing, particularly in stem cells. 

These destabilizing effects of the mitochondria on the nuclear genome of mtDNA mutator mice illustrate the importance of the interplay between nuclear and mitochondrial transcription and translation in health and longevity. This importance was also the focus of a talk by Rebecca McIntyre, a PhD candidate in Riekelt Houtkooper’s lab (Amsterdam University Medical Centers). Dr. Houtkooper’s group used an in silico drug screen to identify mimics of FOXO3, a transcription factor-encoding gene that is consistently associated with human longevity. They found that one of these mimics, a nucleoside reverse transcriptase inhibitor known as zidovudine that is typically used as an antiretroviral treatment, causes downregulation of ribosomal genes both in the mitochondria and in the cytosol. Zidovudine acts on the mitochondrial stress regulator and transcription factor ATF-4, which regulates the ratio of mitochondrial and cytosolic ribosomal proteins. The resulting decrease in translation extends healthy lifespan in C. elegans.

Light-eating worms and WormBot

C. elegans were also front and center in two of the meeting’s most innovate and lively talks. In one of these, Dr. Shahaf Peleg (Research Institute for Farm Animal Biology) presented new work on a photo-activated mitochondrial proton pump known as mtON that allows mutant worms to produce ATP from light. Originally developed by Dr. Andrew Wojtovich (University of Rochester) and colleagues as an optogenetic technique to control the proton-motive force, mtON also extends lifespan and healthspan by reversing the age-associated decline in mitochondrial membrane potential. While the underlying mechanism remains to be verified, restoring the membrane potential may influence the redox metabolites that are known to impact the ageing process. Dr. Peleg and colleagues hope to develop a corresponding mouse model and even envision translational research in the future.

One of Dr. Peleg and Dr. Wojtovich’s collaborators on the mtON longevity study, Dr. Matt Kaeberlein (University of Washington), delivered his own talk showcasing an innovative tool he and colleagues developed called WormBot. This automated, high-throughput screening platform for C. elegans survival analysis produces time lapse videos of 144 culture wells in parallel, allowing for thousands of experiments per year. Dr. Kaeberlein’s group simultaneously evaluated changes in worm longevity in response to dozens of FDA-approved drugs, both alone and in combination with the lifespan-extending metformin. This proof of principle experiment identified several drugs for which the combined effect with metformin was several times greater than the effect of either drug alone. Dr. Kaeberlein also presented an initial analysis of the effects of conserved essential gene expression on replicative lifespan in yeast. In contrast to the standard approach of knocking down or deleting these genes, Dr. Kaeberlein and colleagues overexpressed them. Overexpression increased replicative lifespan for about a third of the nearly 100 essential genes tested, a much higher proportion than is typically found in gene knockdown or deletion studies.

Reproductive longevity in women: a gender equality issue

The fact that reproductive senescence long predates other forms of senescence in female humans is taken for granted. Yet menopause is a trait that we share only with only four other species, all of them whales, suggesting that it may not be a biological imperative. In her thought-provoking talk, Dr. Jennifer Garrison (Buck Institute for Research on Aging, USA) framed women’s reproductive longevity as a matter of gender equality. Menopause is associated with extensive adverse health effects, including an increased risk of osteoporosis, arthritis, stroke, heart disease, weight gain, cognitive decline, and depression. Affecting roughly a billion women each year, it also represents billions of dollars in healthcare and lost productivity costs. Yet, research on women’s health is grossly underfunded, receiving just a fraction of the total NIH budget, with research on women’s reproductive health receiving in turn just a sliver of that fraction. To address this problem, Dr. Garrison and colleagues at the Buck Institute have launched the Center for Reproductive Longevity and Equality, as well as an associated start-up that supports research on reproductive ageing in women. Recently funded work includes studies on the role of the gut microbiome in ovarian ageing, dysfunctional mitochondrial homeostasis in the oocyte, and metabolic reprogramming an ageing ovaries. In addition to providing financial support, the Center should by its very existence help combat the persistent societal taboos around discussions of women’s reproductive health that Dr. Garrison decries as hindering progress in this field.

For those interested, more information on the meeting can be found at https://www.agingpharma.org/

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