The new science behind the health benefits of caffeine

By Dr. Liji Thomas, MDReviewed by Danielle Ellis, B.Sc.Oct 9 2024

Study finds that consuming more caffeine may improve heart health.

Systemic lupus erythematosus (SLE) is an autoimmune condition with a polymorphic presentation and a complicated, often life-threatening, course. A recent study published in Rheumatology explored the role of caffeine in mitigating endothelial dysfunction in SLE.

About the study

The study included 31 SLE patients (30 female vs 1 male) without other CVD risk factors, including past or current smoking, CVD, chronic renal failure, abnormal blood sugar or cholesterol levels. The median age was 43 years, and the median duration of the disease was 18 months.

SLE autoantigens and serum complement C3 and C4 levels were determined. A food frequency questionnaire was used to determine caffeine intake.

Circulating endothelial progenitor cells (EPC) percentage was determined in the SLE patient samples. In a second set, blood samples from healthy donors who did not consume caffeine were processed in vitro to count the number of EPC colony-forming units (CFUs).

The samples were then assessed post-SLE-serum treatment, with and without caffeine exposure (at two dosages, 0.5 mM and 1 mM). The SLE sera came from non-caffeine users.

Autophagy and apoptosis were analyzed in EPCs co-cultured with coffee, with or without SLE sera added. The scientists also evaluated the A2AR/SIRT3/AMPK pathway and its relationship to EPC impairment.

In SLE patients

The median EPC percentage was 0.03, and the median caffeine intake was 166 mg/day. Coffee was the major source, contributing a median of 160 mg/day. The lowest EPC percentage was in those on glucocorticoid treatment and those with neuropsychiatric lupus. The higher the daily caffeine intake, the higher the EPC percentage.

In the healthy samples treated with SLE sera

The EPCs cultured with SLE sera showed poor morphology and a reduced number of CFUs compared to non-treated EPCs. They also had impaired colony organization. Caffeine exposure restored colony structure improved EPC morphology, and increased the CFU count.

Autophagy effects

SLE serum treatment caused a reduction in the autophagy-associated molecule LC3-II, which returned to normal with caffeine treatment at either dosage.

The levels of p62, a molecule degraded during autophagy, increased with SLE serum treatment but returned to normal with caffeine, indicating reduced autophagy. These changes persisted despite treatment with the lysosomal inhibitors E64d and pepstatin.

The researchers attributed these phenomena to a dysfunction or blockade of autophagy in SLE. Autophagy is vital to cardiovascular health, and its deficiency may underlie endothelial dysfunction in SLE. Previous studies indicate that increased autophagy speeds up EPC maturation, underlining its key role in the growth of new blood vessels.

Apoptosis effects

Annexin V (AV) and Bcl-2 were evaluated for apoptosis. Similar changes were seen with SLE serum treatment, with an initial increase in the percentage of AV-positive cells, which declined with caffeine exposure. Bcl-2 levels decreased with SLE sera exposure and were restored with caffeine treatment.

Signaling effects

Caffeine also restored the SLE sera-induced increase in A2AR levels (which in turn increased the lowered SIRT3 protein levels and AMPK activity to normal levels). The SIRT3-AMPK pathway is crucial in inhibiting endothelial dysfunction by limiting vascular inflammation. Thus, caffeine might exert its positive effects on endothelial health via this pathway.

Conclusion

Caffeine showed a protective effect on endothelial function in SLE patients and healthy donor EPCs treated with SLE sera.

These results corroborate earlier studies showing that caffeine protects against senescence caused by oxidative stress by activating the A2AR/SIRT3/AMPK pathway. In vitro caffeine exposure improved EPC survival and inhibited apoptosis while promoting autophagy through this signaling pathway.