Scientific Advisory Board Comment By Marvin Edeas and Volkmar Weissig

We invited João Passos because his work fundamentally reshapes how we understand senescence and inflammaging. By placing mitochondria upstream of inflammatory signaling, his research moves the field beyond the concept of damage accumulation toward a systems-level view of aging as a regulated, targetable process.

Mitochondria are not victims of aging. They are its signal generators. Our idea is to place mitochondria at the origin of inflammaging and to reframe senescence as a regulated, targetable program. If mitochondria are upstream of chronic inflammation, then longevity strategies should not focus only on removing senescent cells, but on modulating the signals that create them.

That shift from damage to dialogue is at the heart of the meeting.

From Damage to Dialogue: Mitochondrial Control of Inflammatory Programs in Senescence and Aging

What if aging is not driven by accumulated damage, but by misguided biological conversations?

In this talk, João Passos challenges the traditional view of cellular senescence as an irreversible end state and reframes it as a regulated inflammatory program, actively orchestrated by mitochondria. Far from being passive victims of damage, mitochondria emerge as central signaling hubs, converting cellular stress into chronic inflammation through tightly controlled immune and metabolic pathways.

His work shows that mitochondrial DNA and RNA released into the cytosol are not accidents, but powerful signals that sustain inflammaging via innate immune activation. Going further, new unpublished data reveal that mitochondrial metabolism can directly reprogram inflammatory gene expression through epigenetic mechanisms, positioning mitochondria at the crossroads of immunity, metabolism, and chromatin regulation.

This perspective fits squarely within the philosophy of Targeting Longevity: aging as a failure of coordination, not a failure of parts. By placing mitochondria upstream of senescence-associated inflammation, this work forces a shift in strategy. If inflammation is programmed, then senescence is not simply something to eliminate it is something to modulate, redirect, and time correctly.

Rather than asking how to remove senescent cells, this talk asks a more fundamental question:

Where should we intervene in the aging process to restore dialogue instead of suppressing symptoms?

This contribution sets the tone for Day 1, anchoring the meeting’s ambition to move longevity research away from blunt interventions and toward precision, timing, and systems-level control.

 

Details and visions: By João F. Passos 

Cellular senescence is a stress response in which damaged cells permanently exit the cell cycle and acquire an inflammatory secretory program that influences tissue function, aging, and age-related disease. While senescence can be beneficial in contexts such as development and tissue repair, the accumulation of senescent cells contributes to persistent inflammation and functional decline during aging. Understanding how this inflammatory program is regulated is therefore central to understanding how senescence impacts organismal aging.

In this talk, I will focus on the emerging role of mitochondria as key regulators of inflammatory signaling in senescent cells. We have shown that mitochondrial dysfunction in senescence leads to the release of mitochondrial nucleic acids into the cytosol. Cytosolic mitochondrial DNA activates innate immune signaling to sustain inflammatory gene expression (Victorelli et al., Nature, 2023), and more recently we demonstrated that cytosolic mitochondrial RNA similarly drives inflammation in senescent cells (Victorelli et al., Nature Communications, 2025). These findings place mitochondria upstream of chronic inflammatory signaling in senescence and aging.

Beyond innate immune activation, I will also discuss unpublished work from our laboratory demonstrating that mitochondrial metabolism directly shapes inflammatory gene expression through epigenetic mechanisms during senescence. These data suggest that mitochondrial metabolic pathways influence chromatin regulation, providing an additional and mechanistically distinct layer of control over inflammatory programs in senescent cells. Together, these observations support a unifying model in which mitochondria act as central hubs integrating innate immune, metabolic, and epigenetic signals to regulate inflammation in senescence and aging.