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Aging can be seen as a physiological progression of biomolecular damage and the accumulation of defective cellular components, which trigger and amplify the process, toward whole-body function weakening. Senescence initiates at the cellular level and consists in an inability to maintain homeostasis, characterized by the overexpression/aberrant expression of inflammatory/immune/stress responses. Aging is associated with significant modifications in immune system cells, toward a decline in immunosurveillance, which, in turn, leads to chronic elevation of inflammation/oxidative stress, increasing the risk of (co)morbidities. Albeit aging is a natural and unavoidable process, it can be regulated by some factors, like lifestyle and diet. Nutrition, indeed, tackles the mechanisms underlying molecular/cellular aging. Many micronutrients, i.e., vitamins and elements, can impact cell function. This review focuses on the role exerted by vitamin D in geroprotection, based on its ability to shape cellular/intracellular processes and drive the immune response toward immune protection against infections and age-related diseases. To this aim, the main biomolecular paths underlying immunosenescence and inflammaging are identified as biotargets of vitamin D. Topics such as heart and skeletal muscle cell function/dysfunction, depending on vitamin D status, are addressed, with comments on hypovitaminosis D correction by food and supplementation. Albeit research has progressed, still limitations exist in translating knowledge into clinical practice, making it necessary to focus attention on the role of vitamin D in aging, especially considering the growing number of older individuals.

The prostacyclin analogue iloprost is used to treat vascular alterations and digital ulcers, the early derangements manifesting in systemic sclerosis (SSc), an autoimmune disease leading to skin and organ fibrosis. Bioindicator(s) of SSc onset and progress are still lacking and the therapeutic approach remains a challenge. The T helper 1 (Th1) chemokine interferon (IFN)γ-induced protein 10 (IP-10/CXCL10) associates with disease progression and worse prognosis. Endothelial cells and fibroblasts, under Th1-dominance, release CXCL10, further enhancing SSc's detrimental status. We analyzed the effect of iloprost on CXCL10 in endothelial cells, dermal fibroblasts, and in the serum of SSc patients. Human endothelial cells and dermal fibroblasts activated with IFNγ/Tumor Necrosis Factor (TNF)α, with/without iloprost, were investigated for CXCL10 secretion/expression and for intracellular signaling cascade underlying chemokine release (Signal Transducer and Activator of Transcription 1, STAT1; Nuclear Factor kappa-light-chain-enhancer of activated B cells, NF-kB; c-Jun NH 2 -terminal kinase, JNK: Phosphatidyl-Inositol 3-kinase (PI3K)/protein kinase B, AKT; Extracellular signal-Regulated Kinase 1/2, ERK1/2). CXCL10 was quantified in sera from 25 patients taking iloprost, satisfying the American College of Rheumatology (ACR)/European Alliance of Associations for Rheumatology (EULAR) 2013 classification criteria for SSc, and in sera from 20 SSc sex/age-matched subjects without therapy, previously collected. In human endothelial cells and fibroblasts, iloprost targeted CXCL10, almost preventing IFNγ/TNFα-dependent cascade activation in endothelial cells. In SSc subjects taking iloprost, serum CXCL10 was lower. These in vitro and in vivo data suggest a potential role of iloprost to limit CXCL10 at local vascular/dermal and systemic levels in SSc and warrant further translational research aimed to ameliorate SSc understanding/management.

Skeletal muscle damage is a common clinical manifestation of systemic sclerosis (SSc). C-X-C chemokine ligand 10 (CXCL10) is involved in myopathy and cardiomyopathy development and is associated with a more severe SSc prognosis. Interestingly, the phosphodiesterase type 5 inhibitor (PDE5i) sildenafil reduces CXCL10 sera levels of patients with diabetic cardiomyopathy and in cardiomyocytes. Here, we analyzed the levels of CXCL10 in the sera of 116 SSc vs. 35 healthy subjects and explored differences in 17 SSc patients on stable treatment with sildenafil. CXCL10 sera levels were three-fold higher in SSc vs. healthy controls, independent of subset and antibody positivity. Sildenafil treatment was associated with lower CXCL10 sera levels. Serum CXCL10 strongly correlated with the clinical severity of muscle involvement and with creatine kinase (CK) serum concentration, suggesting a potential involvement in muscle damage in SSc. In vitro , sildenafil dose-dependently reduced CXCL10 release by activated myocytes and impaired cytokine-induced Signal transducer and activator of transcription 1 (STAT1), Nuclear factor-κB (NFκB) and c-Jun N-terminal kinase (JNK) phosphorylation. This was also seen in cardiomyocytes. Sildenafil-induced CXCL10 inhibition at the systemic and human muscle cell level supports the hypothesis that PDE5i could be a potential therapeutic therapy to prevent and treat muscle damage in SSc.

Skeletal muscle cells, albeit classified as vitamin D receptor (VDR)-poor cells, are finely controlled by vitamin D through genomic and non-genomic mechanisms. Skeletal muscle constantly undergoes cell remodeling, a complex system under multilevel regulation, mainly orchestrated by the satellite niche in response to a variety of stimuli. Cell remodeling is not limited to satisfy reparative and hypertrophic needs, but, through myocyte transcriptome/proteome renewal, it warrants the adaptations necessary to maintain tissue integrity. While vitamin D insufficiency promotes cell maladaptation, restoring vitamin D levels can correct/enhance the myogenic program. Hence, vitamin D fortified foods or supplementation potentially represents the desired approach to limit or avoid muscle wasting and ameliorate health. Nevertheless, consensus on protocols for vitamin D measurement and supplementation is still lacking, due to the high variability of lab tests and of the levels required in different contexts (i.e., age, sex, heath status, lifestyle). This review aims to describe how vitamin D can orchestrate skeletal muscle cell remodeling and myogenic programming, after reviewing the main processes and cell populations involved in this important process, whose correct progress highly impacts on human health. Topics on vitamin D optimal levels, supplementation and blood determination, which are still under debate, will be addressed.

In the elderly, whole-body health largely relies on healthy skeletal muscle, which controls body stability, locomotion, and metabolic homeostasis. Age-related skeletal muscle structural/functional deterioration is associated with a higher risk of severe comorbid conditions and poorer outcomes, demanding major socioeconomic costs. Thus, the need for efficient so-called geroprotective strategies to improve resilience and ensure a good quality of life in older subjects is urgent. Skeletal muscle senescence and metabolic dysregulation share common cellular/intracellular mechanisms, potentially representing targets for intervention to preserve muscle integrity. Many factors converge in aging, and multifaceted approaches have been proposed as interventions, although they have often been inconclusive. Physical exercise can counteract aging and metabolic deficits, not only in maintaining tissue mass, but also by preserving tissue secretory function. Indeed, skeletal muscle is currently considered a proper secretory organ controlling distant organ functions through immunoactive regulatory small peptides called myokines. This review provides a current perspective on the main biomolecular mechanisms underlying age-dependent and metabolic deterioration of skeletal muscle, herein discussed as a secretory organ, the functional integrity of which largely depends on exercise and myokine release. In particular, muscle-derived interleukin (IL)-6 is discussed as a nutrient-level biosensor. Overall, exercise and vitamin D are addressed as optimal geroprotective strategies in view of their multi-target effects.

The term diabetic cardiomyopathy (DCM) labels an abnormal cardiac structure and performance due to intrinsic heart muscle malfunction, independently of other vascular co-morbidity. DCM, accounting for 50%-80% of deaths in diabetic patients, represents a worldwide problem for human health and related economics. Optimal glycemic control is not sufficient to prevent DCM, which derives from heart remodeling and geometrical changes, with both consequences of critical events initially occurring at the cardiomyocyte level. Cardiac cells, under hyperglycemia, very early undergo metabolic abnormalities and contribute to T helper (Th)-driven inflammatory perturbation, behaving as immunoactive units capable of releasing critical biomediators, such as cytokines and chemokines. This paper aims to focus onto the role of cardiomyocytes, no longer considered as "passive" targets but as "active" units participating in the inflammatory dialogue between local and systemic counterparts underlying DCM development and maintenance. Some of the main biomolecular/metabolic/inflammatory processes triggered within cardiac cells by high glucose are overviewed; particular attention is addressed to early inflammatory cytokines and chemokines, representing potential therapeutic targets for a prompt early intervention when no signs or symptoms of DCM are manifesting yet. DCM clinical management still represents a challenge and further translational investigations, including studies at female/male cell level, are warranted.