SRT1720

Intranasal inhalation of the vaccinia virus in mice leads to acute lung infection followed by peripheral organ damage. Our findings demonstrate that hypothyroidism significantly exacerbates disease severity. Hypothyroid mice exhibit higher disease scores, elevated lung viral loads, and more extensive tissue damage in both the lungs and peripheral organs. Notably, only hypothyroid mice reach the experimental endpoint, underscoring their heightened vulnerability. Hypothyroid mice display a defective splenic immune response, with no amplification of T and B lymphocytes, but the increased susceptibility to vaccinia virus infection also persists in hypothyroid lymphocyte-deficient Rag2 -/- mice. Prior to infection, hypothyroid mice show a reduced pool of lung alveolar macrophages, and lung viral loads are significantly elevated in these animals as early as 1 day post-infection, suggesting that an impaired innate immune response is involved in their increased susceptibility to vaccinia virus. Indeed, transfer of primary alveolar macrophages into the alveolar macrophage-deficient lungs of hypothyroid mice significantly alleviates disease symptoms. In euthyroid mice, circulating thyroid hormone levels decrease during infection, a well-documented response in sepsis and critical illness, known as non-thyroidal illness syndrome. Further highlighting the link between thyroid hormones and immune defense, we show that SRT1720, a Sirtuin 1 activator, reduces thyroid hormone levels and also worsens vaccinia infection when administered to euthyroid mice. In summary, our study reveals that hypothyroidism aggravates vaccinia virus infection. While the role of thyroid hormone decline in various diseases remains a topic of debate, our results suggest that thyroid hormones play a protective role in viral pulmonary infections.

Vaccinia virus serves both as a recombinant vaccine platform and as a model for studying human smallpox and monkeypox infections, which are associated with high mortality rates. Here, we show that hypothyroidism in mice aggravates the severity of vaccinia virus infection due to a deficient splenic immune response and to a marked reduction in lung alveolar macrophages, a key cell population in defense against respiratory pathogens. Intratracheal administration of primary alveolar macrophages improves disease symptoms during the early phase of infection in hypothyroid animals. Hypothyroidism also impairs the amplification of splenic lymphocytes, which play a key role in defense against viral infection. Furthermore, vaccinia virus infection reduces thyroid hormone levels in euthyroid mice, a phenomenon named “non-thyroidal illness syndrome” that often occurs in septic patients, suggesting that, in the context of viral pulmonary infections, thyroid hormone replacement might be a useful therapeutic option.

The AMPK/SIRT1/PGC‐1α pathway serves as a central regulator of cellular energy homeostasis, coordinating metabolic stress responses, epigenetic modifications, and transcriptional programs. Its dysfunction is implicated in the pathogenesis of a wide spectrum of complex modern diseases, spanning neurodegeneration, metabolic syndromes, and chronic inflammatory conditions. This review examines the pathway's role as an integrative hub and its potential as a therapeutic target.

We synthesize current mechanistic evidence from molecular, cellular, and preclinical studies to elucidate the pathway's operational logic and the consequences of its dysregulation. The analysis is structured around key disease paradigms—including Alzheimer's disease, Parkinson's disease, diabetes, cardiovascular injury, stroke, and chronic kidney disease—to dissect its tissue‐specific pathophysiological impacts.

The AMPK/SIRT1/PGC‐1α axis operates through a core positive feedback loop: AMPK activation elevates NAD+, thereby activating SIRT1, which in turn deacetylates and activates PGC‐1α to drive mitochondrial biogenesis and function, further reinforcing SIRT1 activity. Disruption of this cascade manifests in disease‐specific mechanisms: promoting Aβ production via BACE1/γ‐secretase in Alzheimer's; impairing α‐synuclein clearance in Parkinson's; disrupting GLUT4 translocation and insulin signaling in diabetes; exacerbating oxidative damage and mitochondrial dysfunction in cardiovascular and neuronal injury; and accelerating fibrosis and sustained inflammation in renal and pulmonary diseases via NLRP3 and TGF‐β/Smad3 signaling.

The AMPK/SIRT1/PGC‐1α pathway represents a cornerstone target at the intersection of metabolism, aging, and disease. Current therapeutic strategies—including pharmacological activators (e.g., metformin, SRT1720), natural compounds (e.g., resveratrol), lifestyle interventions (e.g., exercise, caloric restriction), and emerging technologies (e.g., gene editing, exosomal miRNAs)—offer multidimensional avenues for intervention. Future research must prioritize elucidating tissue‐specific regulatory mechanisms, such as AMPK isoform diversity and PGC‐1α interactome dynamics, to enable precision therapeutics and successful clinical translation for a range of complex disorders.