Suzanne Wolff

The Cell-Non-Autonomous Nature of Electron Transport Chain-Mediated Longevity

The life span of C. elegans can be increased via reduced function of the mitochondria; however, the extent to which mitochondrial alteration in a single, distinct tissue may influence aging in the whole organism remains unknown. We addressed this question by asking whether manipulations to ETC function can modulate aging in a cell-non-autonomous fashion. We report that the alteration of mitochondrial function in key tissues is essential for establishing and maintaining a prolongevity cue. We find that regulators of mitochondrial stress responses are essential and specific genetic requirements for the electron transport chain (ETC) longevity pathway. Strikingly, we find that mitochondrial perturbation in one tissue is perceived and acted upon by the mitochondrial stress response pathway in a distal tissue. These results suggest that mitochondria may establish and perpetuate the rate of aging for the whole organism independent of cell-autonomous functions.

PHA-4/Foxa mediates diet-restriction-induced longevity of C. elegans

Reduced food intake as a result of dietary restriction increases the lifespan of a wide variety of metazoans and delays the onset of multiple age-related pathologies. Dietary restriction elicits a genetically programmed response to nutrient availability that cannot be explained by a simple reduction in metabolism or slower growth of the organism. In the nematode worm Caenorhabditis elegans, the transcription factor PHA-4 has an essential role in the embryonic development of the foregut and is orthologous to genes encoding the mammalian family of Foxa transcription factors, Foxa1, Foxa2 and Foxa3. Foxa family members have important roles during development, but also act later in life to regulate glucagon production and glucose homeostasis, particularly in response to fasting. Here we describe a newly discovered, adult-specific function for PHA-4 in the regulation of diet-restriction-mediated longevity in C. elegans. The role of PHA-4 in lifespan determination is specific for dietary restriction, because it is not required for the increased longevity caused by other genetic pathways that regulate ageing.

SMK-1, an Essential Regulator of DAF-16-Mediated Longevity

Insulin/IGF-1 signaling (IIS) regulates aging in worms, flies, and mice through a well-characterized, highly conserved core set of components. IIS also regulates early developmental decisions, the reproductive status of the animal, innate immunity, and stress-resistance functions. In C. elegans, the sole insulin/IGF-1 receptor, DAF-2, negatively regulates the FOXO transcription factor, DAF-16. We report here on a new component of the IIS longevity pathway, SMK-1, which specifically influences DAF-16-dependent regulation of the aging process in C. elegans by regulating the transcriptional specificity of DAF-16 activity. Localization analysis of DAF-16 places SMK-1 downstream of DAF-16s phosphorylation-dependent relocation to the nucleus. Physiological and transcription analyses indicate that smk-1 is required for the innate immune, UV, and oxidative stress but not the thermal stress functions of DAF-16. SMK-1 therefore plays a role in longevity by modulating DAF-16 transcriptional specificity without affecting other processes regulated by IIS.

Differential Scales of Protein Quality Control

Proteins are notorious for their unpleasant behavior-continually at risk of misfolding, collecting damage, aggregating, and causing toxicity and disease. To counter these challenges, cells have evolved elaborate chaperone and quality control networks that can resolve damage at the level of the protein, organelle, cell, or tissue. On the smallest scale, the integrity of individual proteins is monitored during their synthesis. On a larger scale, cells use compartmentalized defenses and networks of communication, capable sometimes of signaling between cells, to respond to changes in the proteomes health. Together, these layered defenses help protect cells from damaged proteins.

The trifecta of aging in Caenorhabditis elegans.

Insulin signaling, mitochondrial respiration, and dietary restriction share conserved roles not only in the regulation of lifespan, but also in the timing and control of diverse functions such as reproduction, stress resistance and metabolism. These autonomous pathways differ in their dependence on known transcription factors and in their temporal requirements, but converge to manipulate the core set of physiological systems necessary for extended lifespan in worms. Recent work suggests that components of these pleiotrophic pathways might be manipulated specifically for their effects on aging without affecting additional downstream functions. Examination of these findings will help us to understand how the molecular mechanisms of distinct pathways can unite in the regulation of longevity.

HSF-1-mediated cytoskeletal integrity determines thermotolerance and life span

The conserved heat shock transcription factor–1 (HSF-1) is essential to cellular stress resistance and life-span determination. The canonical function of HSF-1 is to regulate a network of genes encoding molecular chaperones that protect proteins from damage caused by extrinsic environmental stress or intrinsic age-related deterioration. In Caenorhabditis elegans, we engineered a modified HSF-1 strain that increased stress resistance and longevity without enhanced chaperone induction. This health assurance acted through the regulation of the calcium-binding protein PAT-10. Loss of pat-10 caused a collapse of the actin cytoskeleton, stress resistance, and life span. Furthermore, overexpression of pat-10 increased actin filament stability, thermotolerance, and longevity, indicating that in addition to chaperone regulation, HSF-1 has a prominent role in cytoskeletal integrity, ensuring cellular function during stress and aging. A transcription factor may promote longevity by stabilizing the actin cytoskeleton in nematodes. Cytoskeleton protects from stress and aging The transcription factor HSF-1 has an unexpected second function that allows it to extend longevity in worms. Baird et al. expressed a modified form of HSF-1 in nematodes. The modified protein could not activate genes encoding protein chaperones. Such chaperones are thought to protect many cellular proteins from heat shock and other damage during aging However, the modified protein still extended the worm life span by regulating the transcription of other genes. One gene it regulated was pat-10, which encodes a troponin-like calcium binding protein. Overexpression of PAT-10 also extended worm life span, apparently by changing the stability of the actin cytoskeleton. Science, this issue p. 360

Lipid Biosynthesis Coordinates a Mitochondrial-to-Cytosolic Stress Response.

Defects in mitochondrial metabolism have been increasingly linked with age-onset protein-misfolding diseases such as Alzheimers, Parkinsons, and Huntingtons. In response to protein-folding stress, compartment-specific unfolded protein responses (UPRs) within the ER, mitochondria, and cytosol work in parallel to ensure cellular protein homeostasis. While perturbation of individual compartments can make other compartments more susceptible to protein stress, the cellular conditions that trigger cross-communication between the individual UPRs remain poorly understood. We have uncovered a conserved, robust mechanism linking mitochondrial protein homeostasis and the cytosolic folding environment through changes in lipid homeostasis. Metabolic restructuring caused by mitochondrial stress or small-molecule activators trigger changes in gene expression coordinated uniquely by both the mitochondrial and cytosolic UPRs, protecting the cell from disease-associated proteins. Our data suggest an intricate and unique system of communication between UPRs in response to metabolic changes that could unveil new targets for diseases of protein misfolding.

SMK-1/PPH-4.1–mediated silencing of the CHK-1 response to DNA damage in early C. elegans embryos

During early embryogenesis in Caenorhabditis elegans, the ATL-1–CHK-1 (ataxia telangiectasia mutated and Rad3 related–Chk1) checkpoint controls the timing of cell division in the future germ line, or P lineage, of the animal. Activation of the CHK-1 pathway by its canonical stimulus DNA damage is actively suppressed in early embryos so that P lineage cell divisions may occur on schedule. We recently found that the rad-2 mutation alleviates this checkpoint silent DNA damage response and, by doing so, causes damage-dependent delays in early embryonic cell cycle progression and subsequent lethality. In this study, we report that mutations in the smk-1 gene cause the rad-2 phenotype. SMK-1 is a regulatory subunit of the PPH-4.1 (protein phosphatase 4) protein phosphatase, and we show that SMK-1 recruits PPH-4.1 to replicating chromatin, where it silences the CHK-1 response to DNA damage. These results identify the SMK-1–PPH-4.1 complex as a critical regulator of the CHK-1 pathway in a developmentally relevant context.

Ageing: Beneficial miscommunication

Natural variations in the rate of protein translation in cellular organelles called mitochondria have been found to correlate with lifespan, suggesting a unified mechanism for the effects of metabolic alterations on longevity. See Article p.451 Animals vary dramatically in lifespan, but why is not clear. Here Johan Auwerx and colleagues report how natural variation in mitochondrial ribosome protein expression translates to lifespan extension in mice and worms, and suggest a unified mechanism behind the effects of metabolic perturbations on longevity. They looked for genetic variation linked to longevity in the BXD genetic reference population of inbred mouse strains. Longevity mapped to mitochondrial ribosomal proteins. Using mouse population genetics and RNA interference experiments in Caenorhabditis elegans, mitochondrial ribosomal protein S5 (Mrps5) and other mitochondrial ribosomal proteins were identified as metabolic and longevity regulators.

Cell biology: The stressful influence of microbes

An investigation into cellular stress responses reveals how cell compartments called mitochondria use information about the surrounding metabolites and microorganisms to protect themselves from damage. See Letter p.406 Damage to mitochondria, the cellular organelles that generate energy through respiration, triggers various protective programs, but little is known about the signalling pathways that monitor mitochondrial function and couple it to protective measures. Through a genome-wide RNA interference screen in the nematode Caenorhabditis elegans, Gary Ruvkun and colleagues identify 45 genes involved in upregulating the protective pathways following drug-mediated and genetic disruptions to mitochondria. Pathways affected by these genes and linked to surveillance include biosynthesis of the signalling lipid ceramide, and the mevalonate pathway (inhibited by the cholesterol-lowering statins).