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METHAMPHETAMINE USE INDEPENDENTLY PREDICTS PREMATURE AGING IN HIV+ INDIVIDUALS
Sanjay R. Mehta1, Jennifer Iudicello1, Ronald J. Ellis1, Jue Lin2, Erin Morgan1, Debralee Cookson1, Robert K. Heaton1, Igor Grant1, Scott L. Letendre1
1University of California San Diego, La Jolla, CA, USA,2University of California San Francisco, San Francisco, CA, USA
As HIV+ adults grow older, aging-related comorbidities occur more frequently than in age-matched controls. Little is known about the role of substance use, which is common in this population, in this 'premature' aging process. We examined the effects of methamphetamine (METH) dependence and HIV on physiologic and functional measures of aging.
Using clinical, demographic and laboratory measures obtained from 124 participants (HIV-/METH- n=31, HIV-/METH+ n=24, HIV+/METH- n=35, HIV+/METH+ n=34), we examined the impact of HIV serostatus and METH dependence in relation to epigenetic changes (telomere to single copy gene ratio [T/S], mitochondrial DNA [mtDNA] level, and relative abundance of the mitochondrial common deletion within the mtDNA population [RACD]) as well as to functional status, cardiovascular comorbidity (Framingham risk scores), renal functional changes, and age-related anthropometric (hip/waist ratio) changes.
Controlling for age, HIV was associated with a lower Karnofsky rating (p<0.001), a larger hip/waist ratio (p=0.052), higher creatinine (p=0.002), and shorter T/S ratio (p=0.003). Similarly, controlling for age, METH use was associated with a shorter T/S ratio (p=0.002) but a lower creatinine (p=0.029). In multivariate regression including HIV, METH, and age, both METH+ and HIV+ remained significant predictors of shorter T/S ratios. In this model and within our study cohort, a 40-year-old HIV+/METH+ individual had a T/S ratio equivalent to a 44.5-year-old HIV+/METH-, a 45.2-year-old HIV-/METH+, and a 60.7-year-old HIV-/METH- individual. When examining RACD, another epigenetic marker of aging, METH+ participants had significantly smaller RACD (p=0.034) only in the HIV seronegative group. In a multivariate regression of creatinine adjusting for age and body mass index, both HIV and METH remained statistically significant, while tenofovir exposure was not a predictor of creatinine level.
Both HIV and METH contribute to premature biological aging with HIV having broader physiologic and epigenetic effects than METH. Consistent with earlier observations, METH was associated with less mtDNA damage, possibly due to induction of autophagy and cell turnover. This may explain the association with improved renal function in METH users, as mitochondrial dysfunction is known to play a significant role in renal disease.