Biology subjects

Harinath, G.

Publications and source records attributed to Harinath, G..

5 recordsLinked to original sources

bioRxiv2022

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

Aging is characterized by declining health that results in decreased neuromuscular function and cellular resilience. The relationship between lifespan and health, and the influence of genetic background on that relationship, has important implications in the development of anti-aging interventions. Here we combined survival under thermal and oxidative stress with swimming performance, to evaluate health effects across a nematode genetic diversity panel for three compounds previously studied in the Caenorhabditis Intervention Testing Program - NP1, propyl gallate, and resveratrol. We show that oxidative stress resistance and thermotolerance vary with compound intervention, genetic background, and age. The effects of tested compounds on swimming locomotion, in contrast, are largely species-specific. Additionally, thermotolerance, but not oxidative stress or swimming ability, correlates with lifespan. Our results demonstrate the importance of assessing health and lifespan across genetic backgrounds in the effort to identify reproducible aging interventions.

physiology↗

bioRxiv2021

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

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: 17-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.

physiology↗

bioRxiv2020

Spaceflight Affects Neuronal Morphology and Alters Transcellular Degradation of Neuronal Debris in Adult Caenorhabditis elegans

Extended space travel, such as crewed missions to Mars and beyond, is a goal for both government space agencies and private companies. Research over the past decades, however, has shown that spaceflight poses risks to human health, including negative effects on musculoskeletal, cardiovascular, and immune systems. Details regarding effects on the nervous system have been less well described. The use of animal models holds great potential to identify and dissect conserved mechanisms of neuronal response to spaceflight. Here, we exploited the unique experimental advantages of the nematode Caenorhabditis elegans to explore how spaceflight affects adult neurons in vivo, at the single-cell level. We found that animals that lived 5 days of their adult life on the International Space Station exhibited considerable dendritic remodeling of the highly branched PVD neuron and modest morphological changes in touch receptor neurons when compared to ground control animals. Our results indicate hyperbranching as a common response of adult neurons to spaceflight. We also found that, in the presence of a neuronal proteotoxic stress, spaceflight promotes a remarkable accumulation of neuronal-derived waste in the surrounding tissues (especially hypodermis), suggesting an impaired transcellular degradation of debris that is released from neurons. Overall, our data reveal that spaceflight can significantly affect adult neuronal morphology and clearance of neuronal trash, highlighting the need to carefully assess the risks of long-duration spaceflight on the nervous system and to develop countermeasures to protect human health during space exploration.

neuroscience↗

bioRxiv2019

Automated Lifespan Determination Across Caenorhabditis Strains and Species Reveals Assay-Specific Effects of Chemical Interventions

The goal of the Caenorhabditis Intervention Testing Program is to identify robust and reproducible pro-longevity interventions that are efficacious across genetically diverse cohorts in the Caenorhabditis genus. The project design features multiple experimental replicates collected by three different laboratories. Our initial effort employed fully manual survival assays. With an interest in increasing throughput, we explored automation with flatbed scanner-based Automated Lifespan Machines (ALMs). We used ALMs to measure survivorship of 22 Caenorhabditis strains spanning three species. Additionally, we tested five chemicals that we previously found extended lifespan in manual assays. Overall, we found similar sources of variation among trials for the ALM and our previous manual assays, verifying reproducibility of outcome. Survival assessment was generally consistent between the manual and the ALM assays, although we did observe radically contrasting results for certain compound interventions. We found that particular lifespan outcome differences could be attributed to protocol elements such as enhanced light exposure of specific compounds in the ALM, underscoring that differences in technical details can influence outcomes and therefore interpretation. Overall, we demonstrate that the ALMs effectively reproduce a large, conventionally scored dataset from a diverse test set, independently validating ALMs as a robust and reproducible approach towards aging-intervention screening.

physiology↗

bioRxiv2019

Swim exercise in C. elegans extends neuromuscular and intestinal healthspan, enhances learning ability, and protects against neurodegeneration

Exercise can protect against cardiovascular disease, neurodegenerative disease, diabetes, cancer, and age-associated declines in muscle, immune, and cognitive function. In fact, regular physical exercise is the most powerful intervention known to enhance robustness of health and aging. Still, the molecular and cellular mechanisms that mediate system-wide exercise benefits remain poorly understood, especially as applies to \"off target\" tissues that do not participate directly in training activity. Elaborating molecular mechanisms of whole-animal exercise benefits is therefore of considerable importance to human health. The development of exercise protocols for short-lived genetic models holds great potential for deciphering fundamental mechanisms of exercise trans-tissue signaling during the entire aging process. Here, we report on the optimization of a long-term swim exercise protocol for C. elegans and we demonstrate its benefits to diverse aging tissues, even if exercise occurs only during a restricted phase during early adulthood. We found that multiple daily swim sessions are essential for exercise adaptation in C. elegans, leading to body wall muscle improvements in structural gene expression, locomotory performance, and mitochondrial morphology. Swim exercise training enhances whole-animal health parameters such as mitochondrial respiration and mid-life survival and increases the functional healthspan of pharynx and intestine. Importantly, we show that swim exercise also enhances nervous system health: exercise increases learning ability of adult animals and protects against neurodegeneration in C. elegans models of tauopathy, Alzheimers disease, and Huntingtons disease. An important point is that swim training only during C. elegans early adulthood induces long-lasting systemic benefits that in several cases are still detectable well into mid-life. Overall, our data reveal the broad impact of swim exercise in promoting extended healthspan of multiple C. elegans tissues, underscore the potency of early exercise experience to influence long-term health (even after cessation of exercise), and establish the foundation for exploiting the powerful advantages of this genetic model to dissect the exercise-dependent molecular circuitry that confers long-lasting system-wide health benefits to aging or diseased adults.

neuroscience↗