Biology subjects

Van Raamsdonk, J. M.

Publications and source records attributed to Van Raamsdonk, J. M..

8 recordsLinked to original sources

bioRxiv2025

Multiple Molecular Pathways to Longevity: Opposing Gene Expression Programs Define Distinct Aging Strategies

While aging is the greatest risk factor for the development of neurodegenerative disease, the role of aging in these diseases is poorly understood. Our previous work has shown that targeting aging pathways can be neuroprotective in animal models of neurodegenerative disease. Based on these findings, we believe that by gaining insight into the aging process, that knowledge can be applied to identify novel therapeutic targets for neurodegenerative disease. To advance our understanding of aging, we used a genomics approach to identify genes regulated by multiple lifespan-extending pathways. We performed RNA sequencing on nine long-lived C. elegans mutants representing seven longevity pathways: insulin/IGF-1 signaling, dietary restriction, germline deficiency, impaired chemosensation, reduced translation, elevated mitochondrial ROS, and mild mitochondrial impairment. We found that most pairs of long-lived mutants exhibited a significant overlap in differentially expressed genes. Comparing gene expression across the entire panel of long-lived mutants revealed three distinct longevity groups that could be clearly distinguished by gene expression. Interestingly, two of these groups showed modulation of specific genetic pathways in opposite directions, suggesting that there are multiple alternative strategies to achieving long life. Filtering for genes similarly modulated in at least six mutants identified 196 upregulated and 62 downregulated aging genes. Upregulated genes were enriched in immunity, defense and metabolism, while many downregulated genes impacted translation and gene expression. To assess the ability of these genes to enhance longevity individually, we knocked down the commonly upregulated genes in long-lived mutants and evaluated the resulting effect on lifespan. Using this approach, we identified several genes that affect lifespan individually. Upregulation of at least some of these genes was sufficient to enhance stress resistance and extend lifespan in wild-type worms. Overall, the shared longevity genes identified in this work offer potential targets to promote healthy aging and decrease age-onset disease.

genetics↗

bioRxiv2025

Rejuvenation of white adipose tissue in a longitudinal heterochronic transplantation model

Exposure to a younger system can induce organismal rejuvenation, yet whether all tissues can be rejuvenated and by what mechanisms remains understudied. We performed heterochronic and isochronic transplantation of subcutaneous white adipose tissue (WAT) between young and old mice and longitudinally tracked changes in biological age. Transplantation accelerated tissue aging, and the molecular age of grafts shifted toward that of the host. Most importantly, old WAT was rejuvenated in a young body. Epigenetic and transcriptomic clocks revealed a reduction of predicted age, accompanied by coordinated activation of canonical and previously unrecognized thermogenic pathways. Molecular rejuvenation was further supported by architectural changes toward a youthful state, including reduced lipid droplet size and decreased cellular heterogeneity. Mitochondrial abundance and morphology remained unchanged, while collagen deposition increased. These results demonstrate that WAT biological age is partially reversible and identify molecular and cellular features underlying its rejuvenation

systems biology↗

bioRxiv2024

Mitochondrial superoxide acts in the intestine to extend longevity

Reactive oxygen species (ROS) are highly reactive oxygen containing molecules that are generated by normal metabolism. While ROS can cause damage to the building blocks that make up cells, these molecules can also act as intracellular signals that promote longevity. The levels of ROS within the cell can be regulated by antioxidant enzymes, such as superoxide dismutase (SOD), which converts superoxide to hydrogen peroxide. Interestingly, our previous work has shown that disruption of the mitochondrial SOD gene sod-2 results in increased lifespan, indicating that elevating levels of mitochondrial superoxide can promote longevity. To explore the molecular mechanisms involved, we determined the tissues in which disruption of sod-2 is necessary for lifespan extension and the tissues in which disruption of sod-2 is sufficient to extend lifespan. We found that tissue-specific restoration of SOD-2 expression in worms lacking SOD-2 could partially revert changes in fertility, embryonic lethality and resistance to stress, but did not inhibit the effects of sod-2 deletion on lifespan. Knocking down sod-2 expression using RNA interference specifically in the intestine, but not other tissues, was sufficient to extend longevity. Intestine-specific knockdown of sod-2 also increased resistance to heat stress and while decreasing resistance to oxidative stress. Combined, these results indicate that disruption of sod-2 in neurons, intestine, germline, or muscle is not required for lifespan extension, but that decreasing sod-2 expression in just the intestine extends lifespan. This work defines the conditions required for elevated mitochondrial superoxide to increase longevity.

genetics↗

bioRxiv2024

Mild activation of the mitochondrial unfolded protein response increases lifespan without increasing resistance to stress

The mitochondrial unfolded protein response (mitoUPR) is a stress response pathway that responds to mitochondrial insults by altering gene expression to recover mitochondrial homeostasis. The mitoUPR is mediated by the stress-activated transcription factor ATFS-1. Constitutive activation of ATFS-1 increases resistance to exogenous stressors but paradoxically decreases lifespan. In this work, we determined the optimal levels of expression of activated ATFS-1 with respect to lifespan and resistance to stress by treating constitutively-active atfs-1(et17) worms with different concentrations of RNA interference (RNAi) bacteria targeting atfs-1. We observed the maximum lifespan of atfs-1(et17) worms at full-strength atfs-1 RNAi, which was significantly longer than wild-type lifespan. Under the conditions of maximum lifespan, atfs-1(et17) worms did not show enhanced resistance to stress, suggesting a trade-off between stress resistance and longevity. The maximum resistance to stress in atfs-1(et17) worms occurred on empty vector (0% atfs-1 knockdown). Under these conditions, atfs-1(et17) worms are short-lived. This indicates that constitutive activation of ATFS-1 can increase lifespan or enhance resistance to stress but not both, at the same time. Finally, we determined the timing requirements for ATFS-1 to affect lifespan. We found that knocking down atfs-1 expression only during development is sufficient to extend atfs-1(et17) lifespan, while adult-only knockdown has no effect. Overall, these results demonstrate that constitutively active ATFS-1 can extend lifespan when expressed at low levels and that this lifespan extension is not dependent on the ability of ATFS-1 to enhance resistance to stress.

developmental biology↗

bioRxiv2024

Transcriptomic Hallmarks of Mortality Reveal Universal and Specific Mechanisms of Aging, Chronic Disease, and Rejuvenation

Health is strongly affected by aging and lifespan-modulating interventions, but the molecular mechanisms of mortality regulation remain unclear. Here, we conducted an RNA-seq analysis of mice subjected to 20 compound treatments in the Interventions Testing Program (ITP). By integrating it with the data from over 4,000 rodent tissues representing aging and responses to genetic, pharmacological, and dietary interventions with established survival data, we developed robust multi-tissue transcriptomic biomarkers of mortality, capable of quantifying aging and change in lifespan in both short-lived and long-lived models. These tools were further extended to single-cell and human data, demonstrating common mechanisms of molecular aging across cell types and species. Via a network analysis, we identified and annotated 26 co-regulated modules of aging and longevity across tissues, and developed interpretable module-specific clocks that capture aging- and mortality-associated phenotypes of functional components, including, among others, inflammatory response, mitochondrial function, lipid metabolism, and extracellular matrix organization. These tools captured and characterized acceleration of biological age induced by progeria models and chronic diseases in rodents and humans. They also revealed rejuvenation induced by heterochronic parabiosis, early embryogenesis, and cellular reprogramming, highlighting universal signatures of mortality, shared across models of rejuvenation and age-related disease. They included Cdkn1a and Lgals3, whose human plasma levels further demonstrated a strong association with all-cause mortality, disease incidence and risk factors, such as obesity and hypertension. Overall, this study uncovers molecular hallmarks of mammalian mortality shared across organs, cell types, species and models of disease and rejuvenation, exposing fundamental mechanisms of aging and longevity.

systems biology↗

bioRxiv2022

Exercise preserves fitness capacity during aging through AMPK and mitochondrial dynamics

Exercise is a nonpharmacological intervention that improves health during aging, and a valuable tool in the diagnostics of aging-related diseases. In muscle, exercise transiently alters mitochondrial functionality and metabolism. Mitochondrial fission and fusion are critical effectors of mitochondrial plasticity, which allows a fine-tuned regulation of organelle connectiveness, size and function. Here we have investigated the role of mitochondrial dynamics during exercise in the genetically tractable model Caenorhabditis elegans. We show that in body wall muscle a single exercise session induces a cycle of mitochondrial fragmentation followed by fusion after a recovery period, and that daily exercise sessions delay the mitochondrial fragmentation and fitness capacity decline that occur with aging. The plasticity of this mitochondrial dynamics cycle is essential for fitness capacity and its enhancement by exercise training. Surprisingly, among longevity-promoting mechanisms we analyzed, constitutive activation of AMPK uniquely preserves fitness capacity during aging. As with exercise training, this benefit of AMPK is abolished by impairment of mitochondrial fission or fusion. AMPK is also required for fitness capacity to be enhanced by exercise, with our findings together suggesting that exercise enhances muscle function through AMPK regulation of mitochondrial dynamics. Our results indicate that mitochondrial connectivity and the mitochondrial dynamics cycle are essential for maintaining fitness capacity and exercise responsiveness during aging, and suggest that AMPK activation may recapitulate some exercise benefits. Targeting mechanisms to optimize mitochondrial fission and fusion balance, as well as AMPK activation, may represent promising strategies for promoting muscle function during aging. Significance StatementExercise is a powerful anti-aging intervention. In muscle exercise remodels mitochondrial metabolism and connectiveness, but the role of mitochondrial dynamics in exercise responsiveness has remained poorly understood. Working in Caenorhabditis elegans, we find that the mitochondrial dynamics cycle of fission and fusion is critical for fitness capacity, that exercise delays an aging-associated decline in mitochondrial connectiveness and fitness capacity, and that the mitochondrial dynamics cycle is required for the latter benefit. AMPK, which regulates mitochondrial dynamics, is needed for exercise to maintain fitness capacity with age and can recapitulate this exercise benefit. Our data identify the mitochondrial dynamics cycle as an essential mediator of exercise responsiveness, and an entry point for interventions to maintain muscle function during aging.

cell biology↗

bioRxiv2021

The Rab GTPase activating protein TBC-2 extends longevity by facilitating release of FOXO/DAF-16 from endosomes

FOXO transcription factors have been shown to regulate longevity in model organisms and are associated with longevity in humans. To gain insight into how FOXO functions to increase lifespan, we examined the subcellular localization of DAF-16 in C. elegans. We show that DAF-16 is localized to endosomes and that this endosomal localization is increased by the insulin-IGF signaling (IIS) pathway. Endosomal localization of DAF-16 is modulated by endosomal trafficking proteins. Disruption of the Rab GTPase activating protein TBC-2 increases endosomal localization of DAF-16, while inhibition of TBC-2 targets, RAB-5 or RAB-7 GTPases, decreases endosomal localization of DAF-16. Importantly, the amount of DAF-16 that is localized to endosomes has functional consequences as increasing endosomal localization through mutations in tbc-2 reduced the lifespan of long-lived daf-2 IGFR mutants, depleted their fat stores, and DAF-16 target gene expression. Overall, this work identifies endosomal localization as a mechanism regulating DAF-16 FOXO, which is important for its functions in metabolism and aging.

cell biology↗

bioRxiv2020

Multiple genetic pathways regulating lifespan extension are neuroprotective in a G2019S LRRK2 nematode model of Parkinson's disease

BackgroundMutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most frequent cause of late-onset, familial Parkinsons disease (PD), and LRRK2 variants are associated with increased risk for sporadic PD. While advanced age represents the strongest risk factor for disease development, it remains unclear how different age-related pathways interact to regulate LRRK2-driven late-onset PD. FindingsIn this study, we employ a C.elegans model expressing PD-linked G2019S LRRK2 to examine the interplay between age-related pathways and LRRK2-induced dopaminergic neurodegeneration. We find that multiple genetic pathways that regulate lifespan extension can provide robust neuroprotection against mutant LRRK2. However, the level of neuroprotection does not strictly correlate with the magnitude of lifespan extension, suggesting that lifespan can be experimentally dissociated from neuroprotection. Using tissue-specific RNAi, we demonstrate that lifespan-regulating pathways, including insulin/IGF-1 signaling, TOR, and mitochondrial respiration, can be directly manipulated in neurons to mediate neuroprotection. We extend this finding for AGE-1/PI3K, where pan-neuronal versus dopaminergic neuronal restoration of AGE-1 reveals both cell-autonomous and non-cell-autonomous neuroprotective mechanisms downstream of insulin signaling. ConclusionsOur data demonstrate the importance of distinct lifespan-regulating pathways in the pathogenesis of LRRK2-linked PD, and suggest that extended longevity is broadly neuroprotective via the actions of these pathways at least in part within neurons. This study further highlights the complex interplay that occurs between cells and tissues during organismal aging and disease manifestation.

neuroscience↗