New research reveals how disrupted mitochondrial function in cartilage drives skeletal aging through metabolic and signaling imbalances.
Researchers from the University of Cologne have identified a novel mechanistic link between mitochondrial dysfunction and premature skeletal aging, demonstrating that disrupted mitochondrial metabolism in cartilage can provoke a cascade of cellular changes that culminate in tissue degeneration. Published in Science Advances, the study examines how altered metabolic activity in chondrocytes – specialized cartilage cells – initially helps compensate for mitochondrial dysfunction but over time disrupts key regulatory pathways, including mTORC1 signaling, ultimately suppressing autophagy and triggering cell death.
The findings build on earlier evidence that mitochondria are not only vital for ATP generation but also play central roles in biosynthesis and nutrient signaling; their dysfunction is increasingly associated with age-related diseases, including sarcopenia and frailty. By targeting the mitochondrial respiratory chain (mtRC) in a mouse model, the research team was able to track downstream effects within cartilage tissue and characterize the molecular responses that drive early-onset skeletal aging [1].
Longevity.Technology: Mitochondrial dysfunction is increasingly recognized not just as a hallmark of rare genetic disorders, but as a core driver of aging and frailty. This new study links disrupted mitochondrial metabolism in cartilage to accelerated skeletal aging, through a chain of compensatory responses that initially support cell function but ultimately become harmful – triggering reductive metabolic rewiring, chronic mTORC1 activation and impaired autophagy. These are molecular echoes of sarcopenia, where mitochondrial decline, redox imbalance and anabolic stress combine to drive tissue degeneration.
Frailty and sarcopenia are among the most burdensome and limiting aspects of aging – contributing not only to falls and loss of independence, but also to reduced resilience, prolonged recovery and diminished quality of life. As global populations age, addressing these conditions is increasingly viewed as essential to extending not just lifespan but healthspan. Notably, the research highlights how a drop in the NAD⁺/NADH ratio – reflecting reductive stress – contributes to cell death, and how supplementation with an NAD⁺ precursor such as NMN can help restore metabolic balance and rescue chondrocyte survival. That this biology is now being mapped so clearly in skeletal tissue strengthens the case for targeting mitochondrial resilience, redox homeostasis and mTORC1 as key strategies for preserving musculoskeletal health and extending healthspan. It also reinforces the therapeutic potential of NAD⁺ restoration in countering age-related decline – not only in muscle, but across the wider architecture of aging.
From adaptation to pathology
The study employed a mouse model expressing a mutated version of the Twinkle helicase enzyme, which, despite its disarming name, disrupts mitochondrial DNA replication specifically in cartilage cells. This caused a marked reduction in mtRC function, resulting in a compensatory activation of the reverse tricarboxylic acid (TCA) cycle. While this adaptation initially supported biosynthetic needs – particularly amino acid production – it also resulted in chronically elevated mTORC1 signaling, a nutrient-sensing pathway associated with both growth and aging [1].
This hyperactivation of mTORC1, while beneficial in the short term, was shown to suppress autophagic flux and disturb protein and lipid homeostasis. Over time, these disruptions contributed to chondrocyte apoptosis and premature replacement of cartilage with bone tissue – hallmarks of skeletal aging.
The researchers also observed a reductive shift in redox balance, marked by an elevated NADH/NAD⁺ ratio. This redox stress is known to interfere with mitochondrial signaling and cellular metabolism and has previously been implicated in age-related muscle atrophy. Crucially, the study showed that supplementing with nicotinamide mononucleotide (NMN), a precursor to NAD⁺, could partially reverse these effects in cultured cells, improving chondrocyte survival under nutrient-depleted conditions [1].
Implications for aging and mitochondrial therapeutics
Professor Bent Brachvogel, corresponding author of the study, said the findings provide a foundation for thinking differently about how early mitochondrial changes shape tissue decline. “The fundamental processes identified here could establish the basis for new treatment strategies to influence cartilage degeneration and skeletal aging in the context of mitochondrial disorders at an early stage,” he said [2].
The potential therapeutic implications are twofold. Firstly, these findings highlight the importance of mitochondrial health in maintaining tissue integrity during aging – particularly in avascular tissues like cartilage, where metabolic clearance is limited. Secondly, the identification of mTORC1 hyperactivation and reductive stress as key drivers of degeneration points toward modifiable targets, including nutrient-sensing pathways and redox metabolism.
These insights align with existing interest in mTORC1 inhibitors, such as rapamycin, which have shown promise in preclinical models of aging. However, this study adds nuance by demonstrating that a complete suppression of mTORC1 is not necessarily beneficial in the context of mitochondrial dysfunction; rather, a balance must be maintained to support anabolic needs while preventing pathological overactivation.
In tandem, strategies aimed at restoring NAD⁺ levels – whether through NMN, nicotinamide riboside, or other precursors – may offer a route to correcting the metabolic imbalances associated with mitochondrial decline. While much of the focus on NAD⁺ restoration has centered on muscle and brain aging, the current research suggests that cartilage and other connective tissues may also benefit from such interventions.
In addition, although this study used NMN, it is plausible that nicotinamide riboside could yield similar effects by elevating NAD⁺ levels and alleviating reductive stress; however, comparative data in skeletal or cartilage-specific models are currently limited, and further research would be needed to establish whether NR offers equivalent cellular uptake, bioavailability and therapeutic impact in this context.
Wider significance within the aging landscape
Although skeletal aging is often associated with bone loss, the study highlights that cartilage degeneration – and the loss of function within chondrocytes – can precede and contribute to broader structural decline. This has implications not only for individuals with mitochondrial diseases, but also for the general aging population, in whom mitochondrial efficiency naturally declines with age.
By exploring the specific pathways through which metabolic adaptation transitions into degeneration, the study provides a conceptual framework that may extend beyond cartilage to other metabolically sensitive tissues. It also offers a model for exploring how age-related changes in one cell type can influence broader tissue remodeling and function.
As research into the molecular hallmarks of aging continues to evolve, the role of mitochondrial function remains central; this work adds precision to that picture, suggesting that early interventions to support mitochondrial metabolism may offer meaningful benefits for skeletal integrity and longevity.
[1] https://www.science.org/doi/epdf/10.1126/sciadv.ads1842
[2] https://www.uni-koeln.de/en/university/news/news/news-detail/malfunctions-in-mitochondria-influence-skeletal-ageing#news11946
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