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The pathways that impact longevity in the wake of dietary restriction (DR) remain still ill-defined. Most studies have focused on nutrient limitation and perturbations of energy metabolism. We showed that the L-threonine was elevated in Caenorhabditis elegans under DR, and that L-threonine supplementation increased its healthspan. Using metabolic and transcriptomic profiling in worms that were fed with RNAi to induce loss of key candidate mediators. L-threonine supplementation and loss-of-threonine dehydrogenaseincreased the healthspan by attenuating ferroptosis in a ferritin-dependent manner. Transcriptomic analysis showed that FTN-1 encoding ferritin was elevated, implying FTN-1 is an essential mediator of longevity promotion. Organismal ferritin levels were positively correlated with chronological aging and L-threonine supplementation protected against age-associated ferroptosis through the DAF-16 and HSF-1 pathways. Our investigation uncovered the role of a distinct and universal metabolite, L-threonine, in DR-mediated improvement in organismal healthspan, suggesting it could be an effective intervention for preventing senescence progression and age-induced ferroptosis. How dietary restriction increases longevity is still not fully understood. Here, the authors demonstrate that L-threonine is an essential mediator of dietary restriction that prevents age-induced ferroptosis and that dietary supplementation promotes healthy ageing.

Death is the inevitable fate of all living organisms, whether at the individual or cellular level. For a long time, cell death was believed to be an undesirable but unavoidable final outcome of nonfunctioning cells, as inflammation was inevitably triggered in response to damage. However, experimental evidence accumulated over the past few decades has revealed different types of cell death that are genetically programmed to eliminate unnecessary or severely damaged cells that may damage surrounding tissues. Several types of cell death, including apoptosis, necrosis, autophagic cell death, and lysosomal cell death, which are classified as programmed cell death, and pyroptosis, necroptosis, and NETosis, which are classified as inflammatory cell death, have been described over the years. Recently, several novel forms of cell death, namely, mitoptosis, paraptosis, immunogenic cell death, entosis, methuosis, parthanatos, ferroptosis, autosis, alkaliptosis, oxeiptosis, cuproptosis, and erebosis, have been discovered and advanced our understanding of cell death and its complexity. In this review, we provide a historical overview of the discovery and characterization of different forms of cell death and highlight their diversity and complexity. We also briefly discuss the regulatory mechanisms underlying each type of cell death and the implications of cell death in various physiological and pathological contexts. This review provides a comprehensive understanding of different mechanisms of cell death that can be leveraged to develop novel therapeutic strategies for various diseases. Cell death mechanisms: implications for disease therapies Cell death is a complex and interconnected process that plays a crucial role in maintaining tissue homeostasis and preventing disease. There are various types of cell death, including necrosis, apoptosis, autophagy, and others, each with distinct morphological features and molecular mechanisms. Understanding the diverse processes underlying cell death is essential for understanding diseases and developing new therapies. Recent research has focused on characterizing and distinguishing various forms of cell death, thereby advancing our understanding of their roles in health and disease. The complex mechanisms underlying cell death are underscored by the intricate interconnections among different types of cell death and the regulation of these mechanisms through diverse signaling pathways and environmental factors. Further research is necessary to fully characterize and differentiate among the various forms of cell death and their roles in pathological conditions.

Adult stem cells (SCs) are essential for tissue maintenance and regeneration yet are susceptible to senescence during aging. We demonstrate the importance of the amount of the oxidized form of cellular nicotinamide adenine dinucleotide (NAD⁺) and its effect on mitochondrial activity as a pivotal switch to modulate muscle SC (MuSC) senescence. Treatment with the NAD⁺ precursor nicotinamide riboside (NR) induced the mitochondrial unfolded protein response and synthesis of prohibitin proteins, and this rejuvenated MuSCs in aged mice. NR also prevented MuSC senescence in the mdx (C57BL/10ScSn-Dmdmdx/J) mouse model of muscular dystrophy. We furthermore demonstrate that NR delays senescence of neural SCs and melanocyte SCs and increases mouse life span. Strategies that conserve cellular NAD⁺ may reprogram dysfunctional SCs and improve life span in mammals.

The naturally occurring compound urolithin A has been found to promote mitophagy, thereby increasing lifespan in worms and improving skeletal muscle activity in rodents. The biological effects of urolithins remain poorly characterized, despite wide-spread human exposure via the dietary consumption of their metabolic precursors, the ellagitannins, which are found in the pomegranate fruit, as well as in nuts and berries. We identified urolithin A (UA) as a first-in-class natural compound that induces mitophagy both in vitro and in vivo following oral consumption. In C. elegans , UA prevented the accumulation of dysfunctional mitochondria with age and extended lifespan. Likewise, UA prolonged normal activity during aging in C. elegans , including mobility and pharyngeal pumping, while maintaining mitochondrial respiratory capacity. These effects translated to rodents, where UA improved exercise capacity in two different mouse models of age-related decline of muscle function, as well as in young rats. Our findings highlight the health benefits of urolithin A and its potential application in strategies to improve mitochondrial and muscle function.

Mitochondria, ubiquitous double-membrane-bound organelles, regulate energy production, support cellular activities, harbor metabolic pathways, and, paradoxically, mediate cell fate. Evidence has shown mitochondria as points of convergence for diverse cell death-inducing pathways that trigger the various mechanisms underlying apoptotic and nonapoptotic programmed cell death. Thus, dysfunctional cellular pathways eventually lead or contribute to various age-related diseases, such as neurodegenerative, cardiovascular and metabolic diseases. Thus, mitochondrion-associated programmed cell death-based treatments show great therapeutic potential, providing novel insights in clinical trials. This review discusses mitochondrial quality control networks with activity triggered by stimuli and that maintain cellular homeostasis via mitohormesis, the mitochondrial unfolded protein response, and mitophagy. The review also presents details on various forms of mitochondria-associated programmed cell death, including apoptosis, necroptosis, ferroptosis, pyroptosis, parthanatos, and paraptosis, and highlights their involvement in age-related disease pathogenesis, collectively suggesting therapeutic directions for further research. Age-related disease: Role of compromised control of mitochondrial quality Therapies directed at the quality control systems of mitochondria have the potential to preserve cellular health in individuals with age-related diseases. Dongryeol Ryu from Gwangju Institute of Science and Technology in South Korea, Riekelt Houtkooper from the Amsterdam University Medical Center in The Netherlands, and colleagues review how dysfunctional mitochondria, which are responsible for producing energy in cells, contribute to cancer and many neurodegenerative, cardiovascular and metabolic conditions. When mitochondria become damaged or stressed, they can trigger cell death mechanisms via impaired quality-control networks and associated signaling pathways, further exacerbating disease processes. By gaining a deeper understanding of how mitochondrial safeguards help to maintain functional integrity, and the different ways in which mitochondria-associated cell death occurs, researchers may identify new targets for drug development.

Water stress caused by water scarcity has a negative impact on the wine industry. Several strategies have been implemented for optimizing water application in vineyards. In this regard, midday stem water potential (SWP) and thermal infrared (TIR) imaging for crop water stress index (CWSI) have been used to assess plant water stress on a vine-by-vine basis without considering the spatial variability. Unmanned Aerial Vehicle (UAV)-borne TIR images are used to assess the canopy temperature variability within vineyards that can be related to the vine water status. Nevertheless, when aerial TIR images are captured over canopy, internal shadow canopy pixels cannot be detected, leading to mixed information that negatively impacts the relationship between CWSI and SWP. This study proposes a methodology for automatic coregistration of thermal and multispectral images (ranging between 490 and 900 nm) obtained from a UAV to remove shadow canopy pixels using a modified scale invariant feature transformation (SIFT) computer vision algorithm and Kmeans++ clustering. Our results indicate that our proposed methodology improves the relationship between CWSI and SWP when shadow canopy pixels are removed from a drip-irrigated Cabernet Sauvignon vineyard. In particular, the coefficient of determination (R2) increased from 0.64 to 0.77. In addition, values of the root mean square error (RMSE) and standard error (SE) decreased from 0.2 to 0.1 MPa and 0.24 to 0.16 MPa, respectively. Finally, this study shows that the negative effect of shadow canopy pixels was higher in those vines with water stress compared with well-watered vines.

Cellular metabolites, such as acyl-CoA, can modify proteins, leading to protein posttranslational modifications (PTMs). One such PTM is lysine succinylation, which is regulated by sirtuin 5 (SIRT5). Although numerous proteins are modified by lysine succinylation, the physiological significance of lysine succinylation and SIRT5 remains elusive. Here, by profiling acyl-CoA molecules in various mouse tissues, we have discovered that different tissues have different acyl-CoA profiles and that succinyl-CoA is the most abundant acyl-CoA molecule in the heart. This interesting observation has prompted us to examine protein lysine succinylation in different mouse tissues in the presence and absence of SIRT5. Protein lysine succinylation predominantly accumulates in the heart when Sirt5 is deleted. Using proteomic studies, we have identified many cardiac proteins regulated by SIRT5. Our data suggest that ECHA, a protein involved in fatty acid oxidation, is a major enzyme that is regulated by SIRT5 and affects heart function. Sirt5 knockout (KO) mice have lower ECHA activity, increased long-chain acyl-CoAs, and decreased ATP in the heart under fasting conditions. Sirt5 KO mice develop hypertrophic cardiomyopathy, as evident from the increased heart weight relative to body weight, as well as reduced shortening and ejection fractions. These findings establish that regulating heart metabolism and function is amajor physiological function of lysine succinylation and SIRT5.

Urolithin A (UA) is a natural dietary, microflora-derived metabolite shown to stimulate mitophagy and improve muscle health in old animals and in preclinical models of aging 1 . Here, we report the results of a first-in-human clinical trial in which we administered UA, either as a single dose or as multiple doses over a 4-week period, to healthy, sedentary elderly individuals. We show that UA has a favourable safety profile (primary outcome). UA was bioavailable in plasma at all doses tested, and 4 weeks of treatment with UA at doses of 500 mg and 1,000 mg modulated plasma acylcarnitines and skeletal muscle mitochondrial gene expression in elderly individuals (secondary outcomes). These observed effects on mitochondrial biomarkers show that UA induces a molecular signature of improved mitochondrial and cellular health following regular oral consumption in humans. Here the authors report the results of a first-in-human trial with urolithin A in healthy elderly individuals, demonstrating that the compound is well tolerated and bioavailable after oral administration. They also provide clinical data indicating that urolithin A may improve mitochondrial and cellular health in human muscle.

The temperature vegetation dryness index (TVDI) has been commonly implemented to estimate regional soil moisture in arid and semi-arid regions. However, the parameterization of the dry edge in the TVDI model is performed with a constraint to define the maximum water stress conditions. Mismatch of the spatial scale between visible and thermal bands retrieved from remotely sensed data and terrain variations also affect the effectiveness of the TVDI. Therefore, this study proposed a new drought index named the condition vegetation drought index (CVDI) to monitor the temporal and spatial variations of soil moisture status by substituting the land surface temperature (LST) with the modified perpendicular drought index (MPDI). In situ soil moisture observations at crop and pasture sites in Victoria were used to validate the effectiveness of the CVDI. The results indicate that the dry and wet edges in the parameterization scheme of the CVDI formed a better-defined trapezoid shape than that of the TVDI. Compared with the MPDI and TVDI for soil moisture monitoring at crop sites, the CVDI exhibited a performance superior to the MPDI and TVDI in most days where the coefficients of determination (R2) achieved can reach to 0.67 on DOY023, 137, 274 and 0.71 on DOY 322 and reproduced more accurate spatial and seasonal variation of soil moisture. Moreover, the CVDI showed higher correlation with the Australian Water Resource Assessment Landscape (AWRA-L) soil moisture product on temporal scales. The R2 can reach to 0.69 and the root mean square error (RMSE) is also much better than that of the MPDI and TVDI. Overall, it can be concluded that the CVDI appears to be a feasible method and can be successfully used in regional soil moisture monitoring.

The capability to monitor water status from crops on a regular basis can enhance productivity and water use efficiency. In this paper, high-resolution thermal imagery acquired by an unmanned aerial vehicle (UAV) was used to map plant water stress and its spatial variability, including sectors under full irrigation and deficit irrigation over nectarine and peach orchards at 6.12 cm ground sample distance. The study site was classified into sub-regions based on crop properties, such as cultivars and tree training systems. In order to enhance the accuracy of the mapping, edge extraction and filtering were conducted prior to the probability modelling employed to obtain crop-property-specific (‘adaptive’ hereafter) lower and higher temperature references (Twet and Tdry respectively). Direct measurements of stem water potential (SWP, ψstem) and stomatal conductance (gs) were collected concurrently with UAV remote sensing and used to validate the thermal index as crop biophysical parameters. The adaptive crop water stress index (CWSI) presented a better agreement with both ψstem and gs with determination coefficients (R2) of 0.72 and 0.82, respectively, while the conventional CWSI applied by a single set of hot and cold references resulted in biased estimates with R2 of 0.27 and 0.34, respectively. Using a small number of ground-based measurements of SWP, CWSI was converted to a high-resolution SWP map to visualize spatial distribution of the water status at field scale. The results have important implications for the optimal management of irrigation for crops.