In Vivo Chemical Reprogramming Is Associated With a Toxic Accumulation of Lipid Droplets Hindering Rejuvenation

Area of Science:

• Cellular biology
• Aging research
• Mitochondrial biology

Background:

• Partial reprogramming aims to reverse cellular aging.
• Chemical reprogramming cocktails can improve mitochondrial function in aged cells.
• In vivo efficacy of these cocktails in mammals remains untested.

Purpose of the Study:

• To investigate the effects of partial chemical reprogramming on mitochondrial structure and function in aged mouse cells.
• To evaluate the in vivo efficacy and safety of chemical reprogramming cocktails in a mammalian aging model.

Main Methods:

• Characterization of mitochondrial changes in aged mouse fibroblasts treated with chemical reprogramming cocktails.
• In vivo administration of chemical reprogramming cocktails to UM-HET3 mice via osmotic pumps.
• Assessment of transcriptomic age, mitochondrial morphology, lipid accumulation, and body weight.

Main Results:

• Chemical reprogramming increased mitochondrial size, altered cristae morphology, promoted network fusion, and increased movement velocity in vitro.
• Low doses in vivo showed no significant effect on transcriptomic age of kidney/liver tissues or OXPHOS expression.
• High doses led to severe weight loss, euthanasia, significant lipid droplet accumulation, and mitochondrial stress in liver tissues.

Conclusions:

• Partial chemical reprogramming shows potential for improving mitochondrial health in aged cells.
• High-dose administration in vivo induces toxicity, including lipid accumulation and mitochondrial stress.
• Further research is needed to optimize dosage and delivery for safe and effective in vivo rejuvenation.