Event Report: A second Aging, Geroscience and Longevity Symposium

Brooke Zanco
Monash University, Melbourne, Australia

00:05:18 – A dietary sterol trade-off determines lifespan responses to dietary restriction in Drosophila melanogaster females
Diet plays a significant role in maintaining lifelong health. Specifically, lowering the dietary protein: carbohydrate ratio improves lifespan. This has been interpreted as a direct effect of these macronutrients on physiology. However, our recent findings indicate that protein and carbohydrate modify lifespan indirectly by altering the partitioning of limiting amounts of sterols between reproduction and lifespan. We show that shorter lifespans in flies fed on high protein: carbohydrate diets can be rescued by supplementing their food with the micronutrient, cholesterol. This alters the way we interpret the mechanisms of lifespan extension by dietary restriction, highlighting the important principle that life histories can be affected by nutrient-dependent trade-offs that are indirect and independent of the nutrients (often macronutrients) that are the focus of study.

Read the full Research Article here.
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Fernando Monje-Casas
CABIMER/Spanish National Research Council (CSIC), Spain

00:24:25 – Aging at the poles: asymmetric inheritance of spindle microtubule organizing centers
Spindle microtubules nucleate from microtubule-organizing centers (MTOCs) located at its poles and known as spindle pole bodies (SPBs) in budding yeast and centrosomes in higher eukaryotes. The MTOCs duplicate early in the cell cycle and are essential for proper spindle biogenesis, orientation and elongation. Intriguingly, after their duplication, the pre-existent (“old”) and the newly generated (“new”) MTOCs can be differentially distributed during certain asymmetric divisions. Work from our laboratory demonstrated that maintenance of the pre-established SPB fate plays a pivotal role in preserving budding yeast replicative lifespan. Specifically, asymmetric SPB inheritance is required to ensure normal levels of the Sir2 sirtuin, a widely conserved lifespan modulator, and to properly distribute functional mitochondria and protein aggregates, which are selectively retained in the mother cell to reset replicative lifespan in the daughter cell, during cell division. A new study from our group, included in eLife’s Special Issue on “Aging, Geroscience and Longevity”, has recently unveil a novel role of Polo-like kinases, a conserved family of key cell cycle regulatory proteins, in the regulation of non-random MTOC distribution. Defects during asymmetric cell divisions have been associated with tumorigenesis, neurodegeneration and developmental problems. Deciphering the basic mechanisms that regulate these divisions is therefore of utmost relevance to better understand the causes for these diseases.

Read the full Research Article here.

Sara Mouton
European Research Institute for the Biology of Ageing, University Medical Center Groningen, the Netherlands

00:47:03 – A physicochemical perspective of aging
To properly function, the molecules in cells need a specific environment. ERIBA researcher Sara Mouton and colleagues show that the characteristics of this environment changes with ageing. The researchers think this physicochemical aspect of ageing complements the traditional views of ageing that are centered around the molecules themselves.

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Andrey A Parkhitko
Aging Institute of UPMC and the University of Pittsburgh, Pittsburgh, United States

01:06:33 – Tissue-specific manipulations of methionine and tyrosine metabolism extend Drosophila lifespan
Aging is a risk factor for various human pathologies including neurodegenerative diseases. Using targeted high-throughput metabolite profiling in Drosophila melanogaster at different ages, we have demonstrated that methionine and tyrosine metabolism are reprogrammed during aging. Strikingly, we found dramatic differences between control B3 and long-lived O1 and O3 flies for many metabolites associated with methionine metabolism and tyrosine metabolism among those that changed with age. Methionine generates the methyl donor, S-adenosylmethionine (SAM), which is converted via methylation to S-adenosylhomocysteine (SAH). We found that reducing levels of SAH at the whole-organism and tissue-specific level extends life- and healthspan. In addition, we demonstrated that the levels of enzymes in the tyrosine degradation pathway increase with age in wild-type flies. Whole-body and neuronal-specific downregulation of enzymes in the tyrosine degradation pathway significantly extends Drosophila lifespan, causes alterations of metabolites associated with increased lifespan, and upregulates the levels of tyrosine-derived neuromediators. Moreover, feeding wild-type flies with tyrosine increased their lifespan. Mechanistically, we show that suppression of ETC complex I drives the upregulation of enzymes in the tyrosine degradation pathway, an effect that can be rescued by tigecycline, an FDA-approved drug that specifically suppresses mitochondrial translation. In addition, tyrosine supplementation partially rescued lifespan of flies with ETC complex I suppression. Altogether, our study highlights the methionine and tyrosine metabolic pathways as regulators of longevity.

Read the full Research Article here.

Michael Stout
Oklahoma University Health Sciences Center (OUHSC), United States

00:00:04 – Estrogen Receptor a is required for 17a-estradiol to modulate health parameters
Metabolic dysfunction underlies several chronic diseases, many of which are exacerbated by obesity. Dietary interventions can reverse metabolic declines and slow aging, although compliance issues remain paramount. 17α-estradiol treatment improves metabolic parameters and slows aging in male mice. The mechanisms by which 17α-estradiol elicits these benefits remain unresolved. Herein, we show that 17α-estradiol elicits similar genomic binding and transcriptional activation through estrogen receptor α (ERα) to that of 17β-estradiol. In addition, we show that the ablation of ERα completely attenuates the beneficial metabolic effects of 17α-E2 in male mice. Our findings suggest that 17α-E2 may act through the liver and hypothalamus to improve metabolic parameters in male mice. Lastly, we also determined that 17α-E2 improves metabolic parameters in male rats, thereby proving that the beneficial effects of 17α-E2 are not limited to mice. Collectively, these studies suggest ERα may be a drug target for mitigating chronic diseases in male mammals.

Read the full Research Article here.

Yang Lyu
Department of Molecular and Integrative Physiology and Geriatrics Center, University of Michigan, United States

00:20:49​​​​​​ – Serotonin 2A receptor signaling coordinates central metabolic processes to modulate aging in response to nutrient choice
We demonstrated that giving flies a choice of foods changes the serotonin signaling in their brain that is responsible for coordinating metabolism, shortening their lifespan as a result. Such effects are largely independent of the amount of nutrients that are consumed. Moreover, knock-down of glutamate dehydrogenase, a key TCA pathway component, abrogates the effect of dietary choice on lifespan.

Read the full Research Article here.

Huiliang Zhang
Department of Laboratory Medicine and Pathology, University of Washington, United States

00:36:43 – Reduction of elevated proton leak rejuvenates mitochondria in the aged cardiomyocyte
Aging-associated diseases, including cardiac dysfunction, are increasingly common in the population. However, the mechanisms of physiologic aging in general, and cardiac aging in particular, remain poorly understood. Age-related heart impairment is lacking a clinically effective treatment. Using the model of naturally aging mice and rats, we show direct evidence of increased proton leak in the aged heart mitochondria. Moreover, our data suggested ANT1 as the most likely site of mediating increased mitochondrial proton permeability in old cardiomyocytes. Most importantly, the tetra-peptide SS-31 (Elamipretide) prevents age-related excess proton entry, decreases the mitochondrial flash activity, rejuvenates mitochondrial function by direct association with ANT1 and the mitochondrial ATP synthasome, and leads to substantial reversal of diastolic dysfunction. Our results uncover the excessive proton leak as a novel mechanism of age-related cardiac dysfunction and elucidate how SS-31 can reverse this clinically important complication of cardiac aging.

Read the full Research Article here.

Karen Krukowski
University of California San Francisco, United States

00:54:49 – Small molecule cognitive enhancer reverses age-related memory decline in mice
With increased life expectancy age-associated cognitive decline becomes a growing concern, even in the absence of recognizable neurodegenerative disease. The integrated stress response (ISR) is activated during aging and contributes to age-related brain phenotypes. We demonstrate that treatment with the drug-like small-molecule ISR inhibitor ISRIB reverses ISR activation in the brain, as indicated by decreased levels of activating transcription factor 4 (ATF4) and phosphorylated eukaryotic translation initiation factor eIF2. Furthermore, ISRIB treatment reverses spatial memory deficits and ameliorates working memory in old mice. At the cellular level in the hippocampus, ISR inhibition i) rescues intrinsic neuronal electrophysiological properties, ii) restores spine density and iii) reduces immune profiles, specifically interferon and T cell-mediated responses. Thus, pharmacological interference with the ISR emerges as a promising intervention strategy for combating age-related cognitive decline in otherwise healthy individuals.

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Ghada Alsaleh
The Kennedy Institute of Rheumatology, NDORMS, University of Oxford, United Kingdom

01:20:30 – Autophagy as a pathway to rejuvenate immune responses
Older adults are at high risk for infectious diseases such as the recent COVID-19. While most vaccines are less efficacious in older adults, little is known about the molecular mechanisms that underpin this. Autophagy is critical for the maintenance of immune memory in mice. Here, we show induction of autophagy is specifically induced in human vaccine-induced antigen-specificTcells in vivo. Reduced IFNg secretion by vaccine-inducedTcells in older vaccinees correlates with low autophagy. We demonstrate in human cohorts that levels of the endogenous autophagy-inducing metabolite spermidine, fall with age and supplementing it in vitro recovers autophagy and Tcell function. Finally, our data show that endogenous spermidine maintains autophagy via the translation factor eIF5A and transcription factor TFEB. With these findings we have provided evidence for the importance of autophagy in vaccine immunogenicity in older humans and uncovered two novel drug targets that may increase vaccination efficiency in the aging context.

Read the full Research Article here.