HDL-C is considered the "good cholesterol" - yet this study seems to indicate that having higher HDL-C can lead to higher all-cause mortality risk. Based on the graphs there seems to be a somewhat narrow "sweet-spot" of HDL. Perhaps this is because HDL amount is a reflection of HDL functionality and overall health, rather than a determining factor for longevity.
@josefbyrne - thoughts?
While HDL is colloquially referred to as “good cholesterol”, as you and this paper suggest, the picture is more nuanced. Importantly, this observational study shows an association between very high HDL and mortality in patients with coronary artery disease - not that high HDL-C causes mortality in the general population.
The authors adjusted for LDL and trigs, but this may not fully capture atherogenic particle load from other ApoB containing particles like VLDLs. Using other metrics like non-HDL cholesterol or ApoB would more directly capture total atherogenic particle burden, but you'd want to watch out for collinearity with the modeling.
More broadly, clinical trials for drugs intended primarily to raise HDL (e.g. niacin, early CETP inhibitors) generally did not reduce adverse cardiovascular outcomes in proportion to the increase in HDL. Newer CETP inhibitors (e.g. obicetrapib) further complicate the simple “good” versus “bad” framing - it markedly raises HDL-C but also lowers LDL-C, non-HDL-C, ApoB, and Lp(a).
Altogether, HDL may be better viewed as an imperfect marker of broader lipoprotein metabolism and health than as a direct determinant of longevity.