Age-associated changes in human CD4+ T cells point to mitochondrial dysfunction consequent to impaired autophagy
11-18-2019Though mitochondrial number in both naive and memory cells visualized with electron microcopy was similar in older versus younger participants, there were a significantly higher number of autophagosomes, many of them containing undegraded mitochondria, in older individuals.
These findings suggest that older age is associated with persistence of dysfunctional mitochondria in CD4+ T lymphocytes caused by defective mitochondrial turnover by autophagy, which may trigger chronic inflammation and contribute to the impairment of immune defense in older persons.
Dr. Luigi Ferrucci and Dr. Ranjan Sen said, "Human aging is characterized by increased susceptibility to diseases and impaired capacity to handle stress and challenges from the environment, leading to excess morbidity and mortality."
Figure 3. (A) Calculated bioenergetic health index (BHI) from young and old CD4+ T cells. The BHI is derived from calculating a ratio of positive aspects of mitochondrial bioenergetic function (i.e. reserve capacity and ATP-linked respiration) to potentially deleterious aspects of mitochondrial bioenergetic function (i.e. non-mitochondrial oxygen consumption and proton leak). Cellular mitochondrial function was determined using high-resolution respirometry with oligomycin, FCCP, rotenone, and antimycin A. For BHI, one outlier of 14 participants was noted and a comparison of the old and young BHI with this outlier was not significantly different (p=0.19). (B) In further analysis, FACS showed the outlier subject had a higher percentage of total memory CD4+ T cells (59% compared to a range 26-48%) than other participants. Adjusting for the average percentage of memory CD4+ T cells, the calculated the BHI was significantly higher for younger compared to older participants (*p = 0.036). (C) Nonmitochondrial respiration was found to be significantly higher in CD4+ T cells from older compared to younger individuals (*p = 0.049). (D) Reserve capacity was significantly higher in cells from young compared to older participants (*p = 0.045). (A–D) P-values were calculated by Welch’s t-test, a variation of the Student’s t-test that does not make the assumption of equal variance in the two compared samples [55]. Error bars reflect the standard error of the mean (±SEM). N = 7 young, 7 old donors.
One aspect that is increasingly being recognized as important to explain the effect of aging on immune cells, particularly CD8+ T cells, is the role of one of the components responsible for cellular proteostasis, macroautophagy and one of its modalities, mitophagy.
Studies in CD8+ T cells of older individuals have shown lower basal autophagy levels, while autolysosomes accumulate in human CD8+ T cells undergoing replicative senescence in vitro.
In CD4+ T cells, it has also been reported that while autophagy activity is lower in cells from older individuals, it is preserved in cells from the progeny of centenarians, which correlates with improved function.
Experiments of T-cell-specific depletion of Vps34 or Atg7, essential genes for canonical autophagy, lead to accumulation of damaged mitochondria and ROS, showing that T cells depend on autophagy and mitophagy for homeostasis and function.
Mitochondria also contribute to this process by using TCA cycle metabolites for the building of macromolecules, including proteins and lipids as building bricks for new cells, and by producing ROS signaling required for full T cell activation.
The Ferrucci/Sen Research Team concluded, "In conclusion, we found evidence of defective mitochondrial recycling in CD4+ T lymphocytes from older compared to younger persons and some suggestion that the lack of mitochondrial recycling can be attributed to defective autophagy."
Full Text - https://doi.org/10.18632/aging.102438
Correspondence to: Luigi Ferrucci email: ferruccilu@mail.nih.gov and Ranjan Sen email: senra@mail.nih.gov
Keywords: proteomics, mitochondria, autophagy, CD4 T cells +
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