Increased CISD2 expression has been shown to slow aging in mice, and is one of the few longevity-inducing genes robustly identified to date. Increased expression improves liver function, reduces senescent cell inflammatory signaling in skin, and generates a range of other beneficial effects along the way. CISD2 produces numerous changes in aspects of metabolism, including mitochondrial function and calcium transport. Understanding which of these effects are more versus less important, and how exactly they induce improved long-term health, remains a work in progress. Expect to see many more papers akin to the one noted here, a deep dive into the effects of CISD2 expression in one specific tissue.
Age-associated atrial myopathy results in structural remodeling and a disturbance of atrial conductance. Atrial myopathy often precedes atrial fibrillation (AF) and can facilitate AF progression. However, the molecular mechanism linking aging to atrial deterioration remains elusive. CDGSH iron-sulfur domain-containing protein 2 (CISD2) is a mammalian pro-longevity gene. We used Cisd2 knockout (Cisd2KO) and Cisd2 transgenic (Cisd2TG) mice to investigate pathophysiological mechanisms underlying age-related atrial myopathy.
Four findings are pinpointed. Firstly, in both humans and mice, the level of atrial CISD2 declines during natural aging; this correlates with age-associated damage, namely degeneration of intercalated discs, mitochondriaps://en.wikipedia.org/wiki/Mitochondrion”>mitochondria, sarcoplasmic reticulum (SR) and myofibrils. Secondly, in Cisd2KO and naturally aged wild-type mice, Cisd2 deficiency causes atrial electrical dysfunction and structural deterioration; conversely, sustained Cisd2 levels protect Cisd2TG mice against age-related atrial myopathy. Thirdly, Cisd2 plays a vital role in maintaining Ca2+ homeostasis in atrial cardiomyocytes. Cisd2 deficiency disrupts Ca2+ regulation, leading to elevated cytosolic Ca2+, reduced SR Ca2+, impaired store-operated calcium entry, and mitochondrial Ca2+ overload; these compromise mitochondrial function and attenuate antioxidant capability. Finally, transcriptomic analysis reveals that Cisd2 protects the atrium from metabolic reprogramming and preserves into old age a transcriptomic profile resembling a youthful pattern, thereby safeguarding the atrium from age-related injury.
This study highlights Cisd2’s crucial role in preventing atrial aging and underscores the therapeutic potential of targeting Cisd2 when combating age-associated atrial dysfunction, which may lead to the development of strategies for improving cardiac health in aging populations.
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