The coupling between healthspan and lifespan in <i>Caenorhabditis</i> depends on complex interactions between compound intervention and genetic background

Banse, Stephen A.; Jackson, Elizabeth; Sedore, Christine A; Onken, Brian; Hall, David G.; Coleman-Hulbert, Anna L; Huynh, Phu; Garrett, Theo; Johnson, Erik; Harinath, Girish; Inman, Delaney; Guo, Suzhen; Morshead, Mackenzie; Xue, Jian; Falkowski, Ron; Chen, Esteban; Herrera, Christopher; Kirsch, Allie J; Pérez, Viviana; Guo, Max; Lithgow, Gordon J.; Driscoll, Monica; Phillips, Patrick C.

doi:10.1101/2022.01.15.476462

Cited by 3 publications

(1 citation statement)

References 74 publications

(116 reference statements)

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“…The goal of these initial studies was to identify interventions that prolonged lifespan. However, longer lifespan is not always associated with an increase in healthy life expectancy [13][14][15][16]. "Healthy worms" are distinguished by their resilience to exogenous stressors, including oxidative, thermal, or endoplasmic reticulum-specific stress (Figure 1).…”

Section: Increased Longevity Does Not Guarantee Improved Health In Ol...mentioning

confidence: 99%

Considering Caenorhabditis elegans Aging on a Temporal and Tissue Scale: The Case of Insulin/IGF-1 Signaling

Fabrizio,

Alcolei,

Solari

2024

Cells

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The aging process is inherently complex, involving multiple mechanisms that interact at different biological scales. The nematode Caenorhabditis elegans is a simple model organism that has played a pivotal role in aging research following the discovery of mutations extending lifespan. Longevity pathways identified in C. elegans were subsequently found to be conserved and regulate lifespan in multiple species. These pathways intersect with fundamental hallmarks of aging that include nutrient sensing, epigenetic alterations, proteostasis loss, and mitochondrial dysfunction. Here we summarize recent data obtained in C. elegans highlighting the importance of studying aging at both the tissue and temporal scale. We then focus on the neuromuscular system to illustrate the kinetics of changes that take place with age. We describe recently developed tools that enabled the dissection of the contribution of the insulin/IGF-1 receptor ortholog DAF-2 to the regulation of worm mobility in specific tissues and at different ages. We also discuss guidelines and potential pitfalls in the use of these new tools. We further highlight the opportunities that they present, especially when combined with recent transcriptomic data, to address and resolve the inherent complexity of aging. Understanding how different aging processes interact within and between tissues at different life stages could ultimately suggest potential intervention points for age-related diseases.

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Section: Increased Longevity Does Not Guarantee Improved Health In Ol...mentioning

confidence: 99%

Considering Caenorhabditis elegans Aging on a Temporal and Tissue Scale: The Case of Insulin/IGF-1 Signaling

Fabrizio,

Alcolei,

Solari

2024

Cells

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Antioxidants green tea extract and nordihydroguaiaretic acid confer species and strain-specific lifespan and health effects in Caenorhabditis nematodes

Banse,

Sedore,

Johnson

et al. 2023

GeroScience

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The Caenorhabditis Intervention Testing Program (CITP) is an NIH-funded research consortium of investigators who conduct analyses at three independent sites to identify chemical interventions that reproducibly promote health and lifespan in a robust manner. The founding principle of the CITP is that compounds with positive effects across a genetically diverse panel of Caenorhabditis species and strains are likely engaging conserved biochemical pathways to exert their effects. As such, interventions that are broadly efficacious might be considered prominent compounds for translation for pre-clinical research and human clinical applications. Here, we report results generated using a recently streamlined pipeline approach for the evaluation of the effects of chemical compounds on lifespan and health. We studied five compounds previously shown to extend C. elegans lifespan or thought to promote mammalian health: 17α-estradiol, acarbose, green tea extract, nordihydroguaiaretic acid, and rapamycin. We found that green tea extract and nordihydroguaiaretic acid extend Caenorhabditis lifespan in a species-specific manner. Additionally, these two antioxidants conferred assay-specific effects in some studies—for example, decreasing survival for certain genetic backgrounds in manual survival assays in contrast with extended lifespan as assayed using automated C. elegans Lifespan Machines. We also observed that GTE and NDGA impact on older adult mobility capacity is dependent on genetic background, and that GTE reduces oxidative stress resistance in some Caenorhabditis strains. Overall, our analysis of the five compounds supports the general idea that genetic background and assay type can influence lifespan and health effects of compounds, and underscores that lifespan and health can be uncoupled by chemical interventions.

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Mitophagy-promoting agents and their ability to promote healthy-aging

Srivastava,

Gross

2023

Biochemical Society Transactions

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The removal of damaged mitochondrial components through a process called mitochondrial autophagy (mitophagy) is essential for the proper function of the mitochondrial network. Hence, mitophagy is vital for the health of all aerobic animals, including humans. Unfortunately, mitophagy declines with age. Many age-associated diseases, including Alzheimer's and Parkinson's, are characterized by the accumulation of damaged mitochondria and oxidative damage. Therefore, activating the mitophagy process with small molecules is an emerging strategy for treating multiple aging diseases. Recent studies have identified natural and synthetic compounds that promote mitophagy and lifespan. This article aims to summarize the existing knowledge about these substances. For readers’ convenience, the knowledge is presented in a table that indicates the chemical data of each substance and its effect on lifespan. The impact on healthspan and the molecular mechanism is reported if known. The article explores the potential of utilizing a combination of mitophagy-inducing drugs within a therapeutic framework and addresses the associated challenges of this strategy. Finally, we discuss the process that balances mitophagy, i.e. mitochondrial biogenesis. In this process, new mitochondrial components are generated to replace the ones cleared by mitophagy. Furthermore, some mitophagy-inducing substances activate biogenesis (e.g. resveratrol and metformin). Finally, we discuss the possibility of combining mitophagy and biogenesis enhancers for future treatment. In conclusion, this article provides an up-to-date source of information about natural and synthetic substances that activate mitophagy and, hopefully, stimulates new hypotheses and studies that promote healthy human aging worldwide.

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The coupling between healthspan and lifespan in Caenorhabditis depends on complex interactions between compound intervention and genetic background

Cited by 3 publications

References 74 publications

Considering Caenorhabditis elegans Aging on a Temporal and Tissue Scale: The Case of Insulin/IGF-1 Signaling

Considering Caenorhabditis elegans Aging on a Temporal and Tissue Scale: The Case of Insulin/IGF-1 Signaling

Antioxidants green tea extract and nordihydroguaiaretic acid confer species and strain-specific lifespan and health effects in Caenorhabditis nematodes

Mitophagy-promoting agents and their ability to promote healthy-aging

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