Abstract:

Background:
Older adults account for more than 30% of surgical procedures in the United States and experience disproportionately high rates of postoperative complications, mortality, and healthcare utilization. Frailty, which is present in up to half of elderly surgical patients, is strongly associated with adverse outcomes and increased cost. Age-related mitochondrial dysfunction and chronic low-grade inflammation contribute to diminished physiologic resilience, increasing susceptibility to ischemia–reperfusion injury and postoperative neurocognitive complications. Flavanols such as (-)-epicatechin and isoquercetin exhibit anti-inflammatory and mitochondrial-enhancing properties through modulation of NF-κB, NLRP3 inflammasome activity, and PGC-1α/SIRT1-dependent bioenergetic pathways. We conducted a pilot study to evaluate the feasibility and biological effects of short-term preoperative flavanol supplementation in older surgical patients.

Methods:
This nonrandomized before-and-after pilot trial enrolled 24 adults ≥50 years undergoing elective hip or knee arthroplasty. Participants received 14 days of oral supplementation containing standardized (-)-epicatechin (111 mg) and isoquercetin (555 mg) daily before surgery. Primary outcomes included feasibility, adherence, and acceptability. Secondary outcomes were changes in circulating inflammatory biomarkers (interleukin-6 [IL-6], lactate dehydrogenase [LDH]) and blood-based mitochondrial bioenergetics assessed via high-throughput respirometry in peripheral blood mononuclear cells (PBMCs) and platelets. Effect sizes were calculated to inform future trials.

Results:
Adherence was high, with 92% of participants completing all 14 days and ≥93% total capsule completion. Acceptability and satisfaction scores were uniformly high, and no adverse events were reported. PBMC mitochondrial respiration improved, with statistically significant increases in maximal respiration and ATP production, and a strong trend toward higher basal respiration (94.5 to 116.5 pmol/min). ATP-linked respiration increased by ~15 pmol/min, and spare respiratory capacity increased by ~50 pmol/min, corresponding to a 24% rise in ATP production. Approximately 65% of participants demonstrated individual improvement in spare respiratory capacity, consistent with the observed group-level increase. Platelet mitochondrial measures showed small, non-significant group-level declines with heterogeneous responses. IL-6 and LDH did not demonstrate significant changes. Grip strength showed a small, non-significant increase overall, with a trend toward improvement in men.

Conclusions:
Short-term preoperative supplementation with (-)-epicatechin and isoquercetin was feasible, well-tolerated, and associated with improvements in PBMC mitochondrial bioenergetics in older adults awaiting joint replacement. Although systemic inflammatory markers were unchanged, the observed mitochondrial signal and strong feasibility metrics provide effect size estimates and operational support for a larger randomized trial investigating flavanol-based perioperative optimization strategies targeting bioenergetic resilience in aging surgical patients.

Authors

• Byron Fergerson, MD¹
• Tatyana Shekhtman, MS, PMC2-3
• Christine Smith, PhD3-6
• Chloe Delgado Ramirez, BS2-3
• Anthony J. Molina, PhD7
• Stephen Dozier, MD7
• Joseph Mitchell, MD8
• Ryan O-Leary, MD8
• Shahrokh Golshan, PhD3-5

Author Affiliations 

1 Department of Anesthesiology, University of California San Diego, La Jolla, California, USA

2 Department of Family Medicine, University of California San Diego, San Diego, CA, USA.

3 Krupp Center for Integrative Research, Centers for Integrative Health, University of California San Diego, San Diego, CA, USA.

4 Veterans Affairs San Diego Healthcare System, San Diego, CA, USA.

5 Department of Psychiatry, University of California San Diego, San Diego, CA, USA.

6 Center for the Neurobiology of Learning and Memory, University of California Irvine, Irvine, CA, USA.

7 Department of Medicine, University of California San Diego, La Jolla, California, USA

8 Department of Orthopaedic Surgery, University of California San Diego, La Jolla, California, USA

Corresponding Author

Byron Fergerson, MD
Department of Anesthesiology
University of California San Diego
9500 Gilman Drive
La Jolla, CA 92093, USA
Email: bfergerson@health.ucsd.ed

Funding

This work was supported by a grant from the University of California San Diego (UCSD) Krupp Endowed Fund to Dr. Fergerson.