Organelle resilience as a comparative blueprint for longevity

Area of Science:

• Geroscience
• Comparative Biology
• Cellular Biology

Background:

• Molecular hallmarks of aging are known, but lifespan extension interventions lack human translation.
• Aging research often focuses on genomics, neglecting cellular organelle stability crucial for tissue function.
• Proteomic, metabolic, and lipid networks sustaining organelles are underrepresented in genomic/transcriptomic studies.

Purpose of the Study:

• To propose comparative organelle biology as the next frontier in geroscience.
• To investigate how divergent lifespans in mammals correlate with organelle architecture and resilience.
• To identify conserved organelle-level mechanisms supporting cellular function over extended periods.

Main Methods:

• Examining mammals with varying lifespans, prioritizing species evolutionarily close to humans.
• Integrating standardized cellular systems, organelle-resolved multi-omics, and computational analysis.
• Introducing the Comparative Metabolic Longevity Cell Atlas (CMLCA) as a cross-mammalian research platform.

Main Results:

• Longer organismal lifespan necessitates sustained organelle functionality and fidelity.
• Comparative analysis can reveal evolved organelle resilience mechanisms in long-lived species.
• The CMLCA platform facilitates identification of conserved resilience features.

Conclusions:

• Comparative organelle biology is key to understanding aging and longevity.
• Organelle resilience mechanisms are critical for extending healthspan.
• Next-generation geroscience strategies can be informed by studying organelle-level adaptations across species.