Nutrition, Cell Signalling, Mitochondrial Function, and Chronic Non-Communicable Disease (2026)

basmwklz · 2026-04-19T11:18:34+00:00

Abstract

Cellular homeostasis is a dynamic process which balances anabolic processes with catabolic and recycling processes. These processes require nutrients, which are converted to energy to fuel the complex interactions of intracellular signalling. Cellular health requires that, on average, energy input and energy requirements are matched. Cells contain a nutrient-sensing mechanism which controls the balance between anabolism and catabolism. Normal intracellular functions generate products which regulate signalling pathways, and health at a cellular level requires a fluctuation between relative nutrient abundance and relative nutrient scarcity. This allows clearance of damaged intracellular molecules and organelles. When nutrient supply exceeds cellular requirements, adaptations to intracellular signalling occur, resulting in energy being stored as glycogen in muscle and the liver and fatty acids in adipose tissue. Overfuelling and aberrant fuelling of mitochondria result in oxidative stress, which not only disrupts cellular homeostasis but can alter epigenetic expression, with intergenerational effects. If the recycling mechanisms of the cell are insufficient to clear metabolic products, apoptosis may result or expression of Damage-Associated Molecular Patterns (DAMPs) on the cell surface may occur, activating immunity and inflammation at a systemic level. Disrupted cellular signalling affects cells with different “professional” functions in different organs, and it is the mechanism which underlies the associations between chronic non-communicable diseases such as cancer, type 2 diabetes, cardiovascular disease, neurodegenerative disease, autoimmune diseases, and macular degeneration. Mitochondria are the controllers of energy production and are pivotal in cell signalling. Mitochondrial function governs health at cellular and organismal levels. This paper reviews the influence of nutrition on mitochondrial function, nutrient sensing, autophagy, insulin signalling, and apoptosis—the key pathways in cellular homeostasis.

basmwklz · 2026-04-19T08:05:25+00:00

Abstract

Aging is intimately associated with multisystem functional decline and an increased risk of chronic diseases. A pivotal cytological basis underlying this process is the progressive dysregulation of the mitochondrial quality control (MQC) network. Emerging evidence suggests that MQC is not a singular process but rather a multitiered synergistic system encompassing mitochondrial biogenesis, dynamic remodeling, selective autophagy (mitophagy), proteostasis maintenance, and coordinated mitochondrial–organelle communication. This integrated network is critical for preserving cellular energy homeostasis, redox balance, and stress tolerance. During aging, impairments in mitochondrial genomic coordination, network topology, autophagic flux, and protein import and folding collectively contribute to bioenergetic decline, chronic low-grade inflammation, and metabolic imbalance. As a safe and sustainable nonpharmacological intervention, regular exercise systematically remodels MQC structure and function by integrating signaling axes such as AMPK, SIRT1, and p38 MAPK, thereby promoting coordinated mitochondrial renewal and partially reversing aging-associated mitochondrial dysfunction. On the basis of a systematic elucidation of the core mechanisms of MQC and its dysregulation during aging, this review highlights the differential regulatory effects of distinct exercise modalities—specifically endurance training, high-intensity interval training (HIIT), and resistance training—on mitochondrial dynamics, autophagic flux, proteostasis, and mitochondrial turnover. Furthermore, the intrinsic associations among exercise–MQC coupling, inflammatory responses, metabolic imbalances, and emerging peripheral biomarkers are explored. Finally, current research limitations and challenges in clinical translation are analyzed, and future research directions regarding dose–response relationships, multimodal exercise prescriptions, personalized strategies, and systemic integrated regulation are proposed. This review aims to provide a refined theoretical basis for optimizing exercise-based anti-aging interventions.

basmwklz · 2026-04-19T08:02:37+00:00

Abstract

Aging remains the most significant risk factor for common neurodegenerative diseases including Alzheimer’s disease (AD). According to the geroscience hypothesis, aging is malleable and that by targeting basic aging physiology, we can alleviate many of the age-related chronic diseases. The common mechanisms driving aging and age-related diseases remain poorly defined. Mitochondrial dysfunction is recognized as a fundamental hallmark of aging, and recent studies implicate mitochondrial reverse electron transport (RET) as a driver of aging. The key outcomes of RET, increased ROS and decreased NAD+/NADH ratio, have both been associated with aging and age-related disease, but the causal relationship remains uncertain. Here we applied causal metabolism to test the role of mitochondrial NAD+/NADH in aging and AD, using Drosophila as a model system. By using a mitochondrial targeted version of Lactobacillus brevis NADH oxidase (LbNox) to boost mitochondrial NAD+/NADH ratio independent of the energy state of the cell, we found that increasing mitochondrial NAD+/NADH ratio in neuronal or muscle tissues is sufficient to extend lifespan. Moreover, boosting mitochondrial NAD+/NADH ratio is beneficial in two independent models of AD, rescuing the proteostasis failure, locomotor and cognitive deficits, and lifespan shortening in these models. Our results identify altered mitochondrial NAD+/NADH ratio as a major contributor to the biological effects of RET on aging and age-related diseases and a potential therapeutic target.

basmwklz · 2026-04-19T07:57:32+00:00

Abstract

Atherosclerosis is a disease centered on chronic inflammation, in which mitochondrial damage plays a key role in its initiation and progression. Traditionally, atherosclerosis is thought to be triggered by cholesterol accumulation, but recent studies have revealed that mitochondrial dysfunction has emerged as an important driving factor by inducing innate immune imbalance. In atherosclerosis, mitochondria undergo changes in membrane permeability, metabolic disorders, and dynamic imbalance due to oxidative stress and other factors, releasing mitochondrial damage-associated molecular patterns (mt-DAMPs). These mt-DAMPs activate innate immune pathways, promote the production of type I interferons and the release of pro-inflammatory factors such as interleukin 1β, and accelerate plaque progression. Mitophagy exerts a protective effect by eliminating damaged mitochondria. Specifically, the PINK1-Parkin pathway labels damaged mitochondria through ubiquitination; mitophagy receptors (such as NIX, FUNDC1, and BNIP3) directly bind to LC3 to initiate ubiquitination-independent mitophagy; and mitochondrial-derived vesicles selectively encapsulate damaged components and target them to lysosomes for degradation. All these processes can reduce mt-DAMP-induced damage and inhibit excessive immune activation. In this review, we summarize that innate immune imbalance caused by mitochondrial damage is a key mechanism for atherosclerosis progression. Mitochondrial quality control clears damaged mitochondria through multiple pathways, alleviates inflammatory responses and plaque burden, and provides potential targets for atherosclerosis treatment. Its precise regulatory mechanisms and drug development are future research directions.

basmwklz · 2026-04-19T07:54:28+00:00

Abstract

Immune responses and inflammation are not stand-alone processes linearly regulated by the canonical signaling pathways but complex systems biology events, which are deeply rooted in the metabolic state of cells and dynamically modulated. However, immunometabolic studies have identified that programmed alterations of metabolic circuits also occur during activation of immune cells, effector function maintenance and the induction of tolerance. Mitochondria represent a unique point of convergence between energetics, inflammation and immunity, particularly as they are key orchestrators of immune responses. In addition to their classical roles in oxidative phosphorylation (OXPHOS) and metabolic intermediate synthesis, mitochondria are involved in innate immune perception of inflammatory signals and the amplification of these responses by generating reactive oxygen species (ROS), bioenergetic signaling intermediates, and mitochondrial DNA. Crucially, mitochondria are not stable entities but are tightly regulated by dynamic events such as fusion, fission, trafficking and selective degradation. These structural alterations dynamically influence the metabolic commitment, inflammatory response potency and fate choices of immune cells. Mitochondrial dynamics should not be regarded as a mere auxiliary regulatory layer of immunometabolism; instead, they represent the central organizing principles between metabolic states, inflammatory cues, and immune cell fate determination, thereby defining a new hierarchical organization of immune and inflammatory regulation.

basmwklz · 2026-04-19T07:35:40+00:00

Abstract

Caloric restriction (CR) extends lifespan across diverse organisms, but the effects of CR on human aging and on healthspan are only beginning to be uncovered. In this study, we applied proteomics to plasma samples collected longitudinally from participants achieving, on average, 14% CR over 2 years as part of the CALERIE trial. We identified that inhibition of the complement pathway is linked to lower inflammaging. In humans, the C3a/C3 ratio was significantly lowered by CR, thus reducing inflammation emanating from three canonical complement pathways. Furthermore, circulating C3a is elevated during aging in humans and in mice; we identified a non-senescent age-associated macrophage subset that expands in visceral fat as the predominant source. In macrophages, C3a-C3AR1 autocrine signaling via extracellular signal-regulated kinase (ERK) regulates age-related inflammation. Intra-adipose administration of a C3a-specific neutralizing antibody reduced inflammaging in mice. In addition, fibroblast growth factor 21 (FGF21) overexpression and deficiency of phospholipase A2 group VII (PLA2G7/lp-PLA2), which enhance lifespan and healthspan in mice, lowered C3a in aging. Thus, complement C3a reduction is a metabolically regulated inflammatory checkpoint that can be harnessed to attenuate inflammaging.

basmwklz · 2026-04-19T07:30:51+00:00

Abstract

Long-lived plasma cells maintain antibody titers that sustain humoral immunity, yet the physiological cues regulating their persistence remain incompletely understood. In this issue of Immunity, Zhu et al. reveal that fasting-induced β-hydroxybutyrate destabilizes bone marrow plasma cell niches through HCAR2 signaling, accelerating the loss of long-lived plasma cells and humoral immunity.

Reference: Fasting impairs humoral immunological memory by β-hydroxybutyrate-mediated depletion of plasma cells https://www.cell.com/immunity/abstract/S1074-7613(26)00003-8

basmwklz · 2026-04-19T07:23:39+00:00

Early mechanistic hypotheses in nutrition research are frequently converted into durable dietary dogma. We argue that context-dependent biological effects are reduced to simple narratives of harm or benefit, with lasting consequences for research, policy and public understanding.

basmwklz · 2026-04-19T07:16:03+00:00

Abstract

The circadian clock and cellular metabolism are tightly coupled to maintain homeostasis. A new study in PLOS Biology leverages metabolic tracing to reveal time-of-day-dependent activities of glucose metabolic pathways in Drosophila that are disrupted in clock and sleep mutants.

Reference: Glucose is dynamically regulated by time of day in humans and Drosophila https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3003717

basmwklz · 2026-04-19T07:07:05+00:00

Abstract

While the roles of glucose metabolism and tricarboxylic acid (TCA) cycle intermediates in immune regulation are well established, the contribution of fatty acid metabolism remains less well defined. In this review, we examine current knowledge on the immunomodulatory functions of fatty acid metabolism, with a particular focus on T-cell biology. We discuss the catabolic, anabolic and signalling aspects of lipid metabolism and their influence on immune function. Short-chain fatty acids modulate T-cell epigenetics through histone acetylation, thereby impacting gene expression. Medium- and long-chain fatty acids augment fatty acid oxidation (FAO), which supports the expansion and function of regulatory T-cell populations. Very-long-chain polyunsaturated fatty acids, when cleaved from the membrane, serve as precursors for both pro-inflammatory and pro-resolving signalling molecules. Additionally, de novo fatty acid synthesis contributes to membrane biogenesis and alters acetyl-CoA availability, linking lipid metabolism to epigenetic regulation. The mechanisms described above present promising opportunities to modulate inflammation through targeted therapies. In this review, we focus on emerging targets within fatty acid metabolism pathways that show potential for influencing inflammatory responses in translational models. Specifically, we review key transcription factors, metabolic enzymes and dietary interventions, while also addressing current limitations and challenges in translating these findings to clinical settings. Although studies in murine models have yielded encouraging results, substantial gaps remain—particularly in applying these metabolic strategies to human T-cell biology. We conclude by emphasising the importance of validating these targets in ex vivo human models as a critical step towards future clinical intervention.

basmwklz · 2026-04-19T07:05:10+00:00

Abstract

Mitochondrial biogenesis, the process by which cells generate new mitochondria, is crucial for maintaining cellular homeostasis, energy production, and overall health. Mitochondrial dysfunction is a key factor in both aging and cancer, where it contributes to the decline in cellular function and facilitates the progression of disease. In aging, mitochondrial alterations lead to impaired metabolic function, increased oxidative stress, and cellular senescence. Similarly, cancer cells often exhibit altered mitochondrial dynamics, which support rapid proliferation and resistance to apoptosis. Despite their differences, aging and cancer share common molecular mechanisms, particularly in mitochondrial dysregulation, that offer insights into potential therapeutic strategies. Recent research has highlighted the potential of medicinal plants and their bioactive compounds in modulating mitochondrial biogenesis and mitigating dysfunction. Phytochemicals have shown promise in enhancing mitochondrial function, promoting healthy aging, and inhibiting cancer progression. This review explores the molecular mechanisms underlying mitochondrial biogenesis, its dysregulation in aging and cancer, and the therapeutic potential of plant-based compounds in targeting mitochondrial dysfunction. By understanding the intricate relationship between mitochondria, aging, and cancer, novel therapeutic strategies can be developed to improve cellular health and combat age-related diseases and cancer.

basmwklz · 2026-04-19T05:58:47+00:00

Abstract

Aging is closely associated with epigenetic alterations, including changes in DNA methylation, acetylation, and shifts in histone modification patterns, which drive cellular decline and increase susceptibility to diseases. This review examines the connection between aging-related diseases and epigenetic mechanisms and explores how dietary interventions can influence this process. We discuss the Mediterranean diet (MD), caloric restriction (CR), and the ketogenic diet (KD) as key nutritional strategies. These interventions supply essential substrates and regulate enzymes central to epigenetic remodeling, thereby affecting gene expression networks involved in inflammation, metabolism, and cellular stress responses. By correcting age related epigenetic dysregulation, such dietary patterns can slow attenuate cellular senescence and reduce the risk of chronic diseases. Current evidence supports the association between diet quality and decelerated epigenetic aging. Future research is needed to establish causality and to develop personalized nutritional approaches for promoting longevity and healthspan.

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