Background Aging is a multifactorial process that affects multiple tissues and is characterized by changes in homeostasis over time, leading to increased morbidity. Whole blood gene expression signatures have been associated with aging and have been used to gain information on its biological mechanisms, which are still not fully understood. However, blood is composed of many cell types whose proportions in blood vary with age. As a result, previously observed associations between gene expression levels and aging might be driven by cell type composition rather than intracellular aging mechanisms. To overcome this, previous aging studies already accounted for major cell types, but the possibility that the reported associations are false positives driven by less prevalent cell subtypes remains. Results Here, we compared the regression model from our previous work to an extended model that corrects for 33 additional white blood cell subtypes. Both models were applied to whole blood gene expression data from 3165 individuals belonging to the general population (age range of 18–81 years). We evaluated that the new model is a better fit for the data and it identified fewer genes associated with aging (625, compared to the 2808 of the initial model; P ≤ 2.5⨯10−6). Moreover, 511 genes (~ 18% of the 2808 genes identified by the initial model) were found using both models, indicating that the other previously reported genes could be proxies for less abundant cell types. In particular, functional enrichment of the genes identified by the new model highlighted pathways and GO terms specifically associated with platelet activity. Conclusions We conclude that gene expression analyses in blood strongly benefit from correction for both common and rare blood cell types, and recommend using blood-cell count estimates as standard covariates when studying whole blood gene expression.

Aging is an evolutionarily conserved process and is tightly connected to mitochondria. To uncover the aging molecular mechanisms related to mitochondria, different organisms have been extensively used as model systems. Among these, the budding yeast Saccharomyces cerevisiae has been reported multiple times as a model of choice when studying cellular aging. In particular, yeast provides a quick and trustworthy system to identify shared aging genes and pathway patterns. In this viewpoint on aging and mitochondria, I will focus on the mitochondrial permeability transition pore (mPTP), which has been reported and proposed as a main player in cellular aging. I will make several parallelisms with yeast to highlight how this unicellular organism can be used as a guidance system to understand conserved cellular and molecular events in multicellular organisms such as humans. Overall, a thread connecting the preservation of mitochondrial functionality with the activity of the mPTP emerges in the regulation of cell survival and cell death, which in turn could potentially affect aging and aging-related diseases.