Secondary Logo

Journal Logo


Basic science and pathogenesis of ageing with HIV

potential mechanisms and biomarkers

Lagathu, Clairea,b,c; Cossarizza, Andread,*; Béréziat, Véroniquea,b,c; Nasi, Milenae; Capeau, Jacquelinea,b,c,*; Pinti, Marcellof

Author Information
doi: 10.1097/QAD.0000000000001441
  • Free



At the level of whole organism, ageing is defined as a progressive loss of physiological integrity, with heterogeneous organ decline, naturally ending by death. Ageing is associated with decreased ability to face stress, increased frailty, and increased prevalence of age-related comorbidities. All these alterations are connected, and raise the possibility of developing novel multidisease preventive and therapeutic approaches [1]. Ageing rate varies among individuals, because of genetic heterogeneity and environmental factors. Tissue ageing and functional loss define the biological age, which could markedly differ from the chronological one, and is associated with healthy aging. Indeed, in addition to life span, which continues to rise in the general population, it is important to consider ‘healthspan’. Healthy ageing is defined as no major chronic diseases or major impairments in cognitive or physical function or mental health [2] and is not keeping pace with life span [1]. This is of major importance for HIV-infected patients. Even if life span is getting closer to that of the general population, these patients, and mainly the older ones, present an increased prevalence of age-related comorbidities [3], precluding healthspan, and which could result from some enhanced ageing mechanisms. Similarities and dissimilarities exist between HIV-infection and normal ageing. Therefore, an important question is whether ageing mechanisms associated with HIV-infection are similar or not to those observed in the general population [3].

At the cellular level, ageing results from time-dependent accumulation of cellular damage affecting molecules or organelles [4]. Once a certain level of damage is reached, cells undergo temporary cell cycle arrest, apoptosis, or cellular senescence [5].

Here, we present the main ageing mechanisms according to the seven pillars of ageing [1,6] and also to the mechanisms detailed by Lopez-Otin [7] (Fig. 1). We then evaluate their potential role in the ageing process observed in HIV-infected older individuals (Figs 1 and 2).

Fig. 1
Fig. 1:
General and HIV-specific mechanisms of ageing.ART, antiretroviral therapy; CMV, cytomegalovirus; HCV, hepatitis C virus; mtDNA, mitochondrial DNA; NRTIs, nucleoside analogue reverse transcriptase inhibitors; PI, protease inhibitor; SASP, secretory-associated senescence phenotype. Mechanisms enhanced in HIV-infected patients are indicated in red. Mechanisms specific to HIV-infected patients are indicated in white.
Fig. 2
Fig. 2:
Molecular and cellular mechanisms of ageing in HIV-infected patients.Ageing and age-related comorbidities result from multiple mechanisms with inflammation and innate immunity activation probably playing a leading role. These mechanisms are enhanced in response to residual HIV infection and to some ART molecules but also to personal lifestyle factors. ART, antiretroviral therapy; CMV, cytomegalovirus; HCV, hepatitis C virus; NRTIs, nucleoside analogue reverse transcriptase inhibitors; Nef, negative regulatory factor; PIs, protease inhibitors; Tat, transactivator of transcription; Vpr, viral protein r.

Genetics and epigenetics

The genetic contribution to human life span is about 25–30% [8,9], mainly after 60 years [9,10]. The two main loci [11] are APOE encoding apolipoprotein E, involved in lipoprotein metabolism, cognitive function, and immune regulation [12] and forkhead box O3A (FOXO3A) involved in apoptosis and oxidative stress [13]. In addition, genome-wide association studies (GWAS) [14–16] identified new loci as multiple inositol-polyphosphate phosphatase 1 (MINPP1) [17], otolin1 (OTOL1) [18], and calcium/calmodulin dependent protein kinase IV (CAMKIV) [16].

In HIV-infected patients over 60 years, apolipoprotein E4 (APOE4) allele is correlated with decreased cognitive performance, premature brain ageing, and atrophy. APOE4 carriers show a higher frequency of HIV-associated neurocognitive disorders, particularly dementia, suggesting that APOE4 can exacerbate age-related cognitive decline [19].

Mitochondria play a crucial role in ageing. The mitochondrial DNA (mtDNA) C150T mutation is associated with extended life span in Finnish and Japanese individuals [20,21]. Haplogroup J is overrepresented in long-living Italian [22], Irish, and Finnish people [23,24].

In HIV-infected and noninfected patients, some haplogroups were associated with age-related disorders as insulin resistance, cardiovascular diseases, abnormal fat metabolism, and/or distribution. Otherwise, haplogroups J, U5a and HV were associated with accelerated progression to AIDS and CD4+ recovery [25], African haplogroup L2 with poorer CD4+ recovery and lower activation in antiretroviral treatment (ART)-treated non-Hispanic Blacks [26,27], European haplogroup H (and clade HV) with lower likelihood of AIDS progression and improved recovery of CD4+ during ART [28,29].

Ageing is also linked to epigenetic alterations in response to exogenous and endogenous factors [30], leading to an abnormal chromatin condition, genomic instability, and accumulation of DNA mutations [31]. Recently, Horvath [32] proposed that DNA methylation age could measure the cumulative effect of an epigenetic maintenance system. This novel epigenetic clock addresses the biological age in tissues. Both chronic and recent HIV infection in ART-receiving patients led to an average ageing advance of 4.9 years, increasing expected mortality risk by 19%. Specific decreased methylation of the human leucocyte antigen (HLA) locus was predictive of lower CD4+:CD8+ ratio, linking molecular ageing, epigenetic regulation, and disease progression [33]. Adjustment on cytomegalovirus (CMV) infection, which is more prevalent in HIV-infected patients and a major driver of immunosenescence, is required.

Macromolecular damage

Damage to protein, DNA, lipids, and other macromolecular components is an important contributor to specific age-related diseases [34]. DNA modifications can occur spontaneously, or be caused by environmental factors, and accumulate when cell repair system cannot cope with damage [35].

Telomeres, repetitive nucleotide sequences at each chromosome end, protect genome. In the absence of telomerase reverse transcriptase activity, a small portion of telomere sequence is lost after each cell division. When telomere length reaches a critical size, cells undergo senescence and/or apoptosis [36]. Thus, telomere length decreases with age [37] and is associated to age-related diseases and decreased life span [38].

Decreased telomere length was reported in peripheral blood mononuclear cells (PBMC) isolated from ART-naive or ART-controlled HIV-infected patients, compared with noninfected individuals [39,40] and associated with poor immune recovery. Nucleoside analogue reverse transcriptase inhibitors can alter telomerase reverse transcriptase activity, resulting in telomere length shortening [41,42].

Adaptation to stress

Mitochondrial dysfunction and oxidative stress

Progressive mitochondrial dysfunction is a hallmark of ageing [7], and accelerates ageing in high energy-demanding tissues as heart, skeletal muscle, kidney, liver, or brain [43–47]. It mainly results from a reduced ability to cope with reactive oxygen species (ROS). ROS exert positive physiological effects within a narrow range of concentrations, and detrimental effects when excessive. mtDNA is particularly susceptible to oxidative damage because of its proximity to free radical sources and the relative lack of a protein scaffold [48]. ROS generated by respiratory chain cause mtDNA mutations or deletions, leading to impairment in mitochondrial protein synthesis, to loss of oxidative phosphorylation efficiency, and ultimately to premature senescence and ageing [49]. This particularly impacts type II muscle fibers, predominantly lost with ageing [50].

HIV can directly induce mitochondrial ROS production [51,52]. It impairs complex I activity, causing loss of mitochondrial membrane potential and apoptosis [53]. Viral infection per se reduces mtDNA level [54,55]. Some nucleoside analogue reverse transcriptase inhibitors, mainly stavudine and zidovudine, affect mitochondria, in part by inhibiting the DNA polymeraseγ [56], causing mtDNA depletion, mitochondrial dysfunction, oxidative stress, all features shared with ageing. Moreover, some protease inhibitors can increase oxidative stress, because of prelamin A accumulation (see below).

Control of cell death, autophagy

Cell propensity to apoptosis undergoes age-dependent changes, and is altered in several comorbidities [57]. Lymphocytes are continuously exposed to damage, and respond with a series of mechanisms, including apoptosis [58]. Cells from elderly are less prone to damage and ROS-induced apoptosis [59,60], whereas mainly CD4+ and also CD8+ cells are more sensitive to tumor necrosis factor-alpha, (TNFα)-induced apoptosis [61,62]. Activation-induced cell death (AICD) of immune cells is often impaired with ageing, with a progressive increased expression of CD95+, the main mediator of AICD [63].

During HIV infection, chronic immune activation is accompanied by higher expression of TNF superfamily ligands and their receptors, particularly Fas ligand or CD95L and tumor-necrosis-factor-related apoptosis inducing ligand (TRAIL), and higher AICD [64]. Regarding HIV proteins, secreted transactivator of transcription (Tat) upregulates CD95L and TRAIL in T cells or macrophages [65–67], whereas negative regulatory factor (Nef) and glycoprotein 120 (gp120) upregulate CD95L expression [68] resulting in bystander apoptosis of uninfected T cells. Viral protein r (Vpr) can also induce intrinsic T-cells apoptosis, causing a rapid decrease in mitochondrial membrane potential and the release of cytochrome c. As well, Tat downregulates B-cell lymphoma 2 (Bcl-2) [69].

Autophagy is a mechanism through which cargo is sequestered in a double-membrane vesicle, which then delivers the content to a lysosome for degradation [70]. Autophagy declines with ageing, and is a major contributor to this process [71]. Its impairment could accelerate ageing through aberrant nuclear division [72]. Accordingly, in animal models, pharmacological or genetic autophagy enhancement extends life span, whereas its inhibition shortens life span [73–75]. Downregulation of key autophagy genes, as autophagy-related 5 (ATG5) and autophagy-related 7 (ATG7), was reported in human brain ageing [76], and autophagy is altered in age-related neurodegenerative diseases, as Alzheimer and Parkinson diseases [77,78]. Mitophagy, the autophagic mitochondria degradation, is required to guarantee mitochondrial quality control and cell survival [79] and is defective during ageing, leading to the accumulation of dysfunctional mitochondria [80].

Several HIV proteins can interfere with autophagy. Tat alters neuronal autophagy by modulating autophagosome fusion to the lysosome. Its overexpression in mice increased accumulation of autophagosomes in neurons, altered microtubule-associated protein 1A/1B-light chain 3II (LC3II) levels, and induced neurodegeneration [81]. Accordingly, autophagy was downregulated in the brain of aged HIV-infected patients with encephalitis or dementia, and in aged mice overexpressing gp120, whereas activation of autophagy by beclin-1 gene transfer ameliorated the neurodegenerative phenotype [82–84]. Nef inhibits autophagy by interacting with beclin-1, and thereby induces oxidative stress and mesenchymal stem cells (MSC) senescence [85].


Ageing is accompanied by a gradual increase of protein oxidative damage and an imbalance in proteostasis, because of the impairment of protein degradation by the ubiquitin-proteasome system and the low efficiency of autophagy [86]. Misfolded proteins accumulation triggers the ‘unfolded protein response’ (UPR), aimed at restoring the homeostatic equilibrium through upregulation of chaperones and proteases. Both mitochondrial and endoplasmic reticulum UPR declines with age [87,88].

Tat induces the UPR response, along with mitochondria hyperpolarization, in the central nervous system, which can contribute to the cognitive decline of HIV-infected patients [89]. Protease inhibitors activate UPR in hepatocytes and macrophages, with an increased expression of TNFα and interleukin-6 (IL-6), thus promoting the premature onset of cardiovascular diseases [90–92]. Endoplasmic reticulum stress and UPR are induced in intestinal epithelial cells by protease inhibitors, resulting in disruption of the epithelial barrier integrity [93], and in hepatocytes by efavirenz [94].


Human ageing is characterized by a gradually increasing state of low-grade sterile inflammation often referred to as ‘inflammageing’ [95]. The level of systemic biomarkers of inflammation, as C-reactive protein, IL-6, soluble-TNFα receptors, is related to ageing, to the long-term occurrence of morbidity, and to mortality [96]. In controlled HIV-infected patients, increased systemic inflammation and innate immune activation solubleCD14 (sCD14) have been associated with most non-AIDS-related comorbidities, frailty, and mortality [97–99].

Inflammation results from multiple causes. First, damaged macromolecules such as extracellular ATP, excess glucose, ceramides, amyloids, urate, and cholesterol crystals, all of which increase with age [100,101], can mimic bacterial products and function as endogenous ‘damage’-associated molecular patterns that activate innate immunity and the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome pathway, leading to IL-1β and IL-8 release. However, in PBMC from ART-controlled patients, the expression of the inflammasome components was not altered [102].

Second, inflammation can result from cell senescence, a stable cell cycle arrest characterized by a specific secretory-associated senescence phenotype, which includes inflammatory cytokines and extracellular matrix-remodeling proteins [103]. Replicative senescence results from telomere shortening, whereas stress-induced senescence is induced by oxidative stress or damage to organelles. Cell cycle checkpoint proteins are increased, stopping cell division until damage repair, or cell elimination by the immune system. The two main senescence pathways involve cyclin-dependent kinase inhibitor 2A, multiple tumor suppressor 1 (p16INK4a)/retinoblastome and cyclin-dependent kinase inhibitor 1 (p21WAF-1)/protein 53 (p53) [103], p16INK4a being now considered as the main actor controlling ageing and age-related diseases [104]. Senescence can also result from the accumulation of farnesylated prelamin-A (or its truncated form progerin), the precursor of the nuclear protein lamin-A, belonging to the lamina meshwork. This accumulation results from mutations in the gene encoding lamin-A/C, responsible for Hutchinson–Gilford progeria, or from deficiency in the activity of the metalloprotease ZMPSTE24, maturating prelamin-A to lamin-A [105]. During ageing, senescent cells accumulate in some tissues (skin, lung, spleen, endothelium, adipose tissue) [7], which is deleterious in older organisms, and results in decreased tissue function, impaired regeneration, fibrosis, and secretory-associated senescence phenotype-related inflammation [103].

PBMC of naive HIV-infected patients presented features of ageing and senescence, p16INK4a increased expression, and reduced telomere length [39]. In ART-controlled patients, these two markers were associated with lower current CD4+ levels [39]. Tat and Nef activated senescence pathways in MSCs, and induced a proinflammatory profile [85]. In cultured adipocytes and MSCs, first generation protease inhibitors inhibited ZMPSTE24 and caused farnesylated prelamin-A accumulation [106,107], which contributes to premature senescence in tissues of protease inhibitor-treated individuals [108]. As well, endothelial and vascular smooth muscle cells, treated with ritonavir-boosted protease inhibitors, presented, to different extents, features of cell senescence and inflammation [109,110].

Third, inflammation and innate immune activation can result from harmful products, as lipopolysaccharide, produced by oral or gut microbiota, leaking into the blood. The microbiota composition modification during ageing participates to low-grade inflammation [111,112]. In ART-naive and ART-controlled patients, gut microbiota presents dysbiotic features associated with inflammatory markers [113]. The pathway of kynurenine formation from tryptophan, evaluated by the kynurenine/tryptophan ratio [113], is altered. Enrichment in proinflammatory Prevotella and decreased abundance of anti-inflammatory butyrate-producing Firmicutes, are associated with colonic mucosa dendritic and systemic T-cells activation [114]. This could result from increased gut permeability, only partly restored after ART, from the profound Gut-associated lymphoid tissue (GALT) depletion or from residual HIV [115,116]. Importantly, gut epithelial dysfunction, innate immune activation, and inflammation, but not T-cell activation or senescence, can predict mortality in HIV-treated patients with a history of AIDS [117].

Finally, increased inflammation can also result from immune activation by common chronic pathogens as CMV and hepatitis C virus, from inflammatory cytokine production by expanded visceral adipose tissue [118], or from environment-related conditions as smoking.


Nutrient sensing is playing a major role in ageing in most species. Intracellular signaling by insulin and insulin-like growth factor-1 use the same insulin and insulin-like growth factor signaling (IIS) pathway, conserved during evolution. Its activation by nutritional signals exerts negative effects on life span. Important targets, that negatively control life span, are the FOXO family of transcription factors and the mammalian target of rapamycin complexes, involved in autophagy. By contrast, activation by caloric restriction/starvation of two nutrient sensors, AMP-activated protein kinase (AMPK) and sirtuins, favors healthy ageing and prolongs life span. However, this beneficial effect is difficult to be ascertained in humans but prolonged life span is associated with preserved insulin sensitivity. Metformin, activating AMPK and decreasing insulin resistance, increases longevity in several species and decreases overall mortality in humans [119]. In HIV-infected patients, insulin resistance remains frequent [120].

Ageing also involves changes in endocrine, neuroendocrine, and neuronal communications, with dysfunction of the hypothalamopituitary axis, leading to androgen deficiency in men, decreased growth hormone and dehydroepiandrosterone secretion, responsible for loss of muscle and bone mass. Androgen and growth hormone deficiency are commonly reported in HIV-infected patients [121,122].

Ageing and altered gut microbiota are associated with central fat redistribution, further enhancing chronic systemic inflammation. Adipose tissue represents one of our largest organs and exerts numerous roles as energy storage, adipokine and cytokine secretion, and immune functions. Thus, adipose tissue is at the nexus of pathways involved in life span, age-related diseases, inflammation, and metabolism [123,124]. During ageing, accumulation of senescent adipocyte precursors with decreased adipogenesis results in deleterious hypertrophy of existing adipocytes [125,126].

HIV-infected patients receiving first generation ART developed lipodystrophy with peripheral lipoatrophy and sometimes central fat accumulation, associated with fat inflammation and metabolic disorders [127]. Lipodystrophic features are still observed in some patients [128,129]. HIV itself could be involved in the adipose tissue proinflammatory phenotype, as adipose tissue is an HIV reservoir with latently infected cell populations, despite effective ART [130,131]. Ageing and HIV-linked lipodystrophies present similar adipose tissue dysfunction, with low-grade inflammation and extracellular-matrix remodeling, in addition to central fat redistribution, increased visceral and ectopic fat, and dysmetabolic features [127,132].

In vitro, Tat, Nef, and Vpr affect adipocyte differentiation [133–136], and Tat and Nef induced premature senescence of adipose tissue stem cells (personal results). Adipocytes treated with stavudine or zidovudine were senescent with increased p21WAF-1 and p16INK4a expression and prelamin-A accumulated in protease inhibitor-treated cells and adipose tissue from protease inhibitor-treated patients [19,106,108,110,137,138].

Stem cells

Ageing and metabolic disorders could also result from a progressive and irreversible exhaustion of adult stem cells [139,140]. Adult MSCs are specialized repairing cells, capable of differentiation toward multiple lineages (adipose, bone, muscle, endothelium, and so on), mainly present in the bone marrow (BM), but also in blood and adipose tissue.

Inflammatory signals could promote irreversible and premature MSC exhaustion [95]. Indeed, tissue inflammation but also prolonged stresses, as DNA damage, oxidative stress, and mitochondrial dysfunction, result in MSC senescence leading to loss of MSC homeostasis by endless mobilization.

Tat and Nef induce premature senescence of BM-MSC and impair their osteoblastic potential, suggesting the contribution of MSC senescence to osteoporosis [85]. Some protease inhibitors also lead to BM-MSC senescence [107] and could participate to MSC loss.


Immunosenescence involves remodeling in the organization and functionality of the immune system, that renders elderly individuals more prone to infectious diseases and less responsive to vaccination [141]. Regarding innate immunity, neutrophil and monocyte functions (including chemotaxis, intracellular bacterial killing, phagocytosis, and neutrophil extracellular traps formation) are impaired [142], as well as antigen presentation by dendritic cells and macrophages [141]. The number of natural killer cells increases with age, but their cytotoxic function is impaired [143,144].

The adaptive immune system undergoes deeper modifications and remodeling during ageing, with progressive thymic involution and reduction in the output of naive T cells [145], evidenced by the progressive reduction of T cells positive for the T-cell receptor rearrangement excision circles [146]. This decrease is mirrored by increased frequency and oligoclonality of terminally differentiated effector memory re-expressing CD45RA (TEMRA) cells [147]. Many TEMRA cells are anergic, with senescent, cytotoxic, and inflammatory features [148,149]. Regulatory T cells expansion [150] and an inverted CD4+:CD8+ ratio are frequently observed in elderly individuals [151,152], together with CD28 downregulation [153,154]. Many of the CD8+CD28 expanded clones are the result of persistent infection by viruses, especially CMV [155].

B-cell number also decreases with age [141]. Their repertoire is reduced [156], the expression of activation-induced cytidine deaminase is lower [157] and somatic hypermutation and class switch recombination are impaired [158,159].

In chronic HIV infection, persistent inflammation and systemic immune activation [160] cause premature ageing of the immune system [161]. This immune activation results from the persistent gut microbial translocation [162], sustained chronic antigenic stimulation, low-level HIV viremia [163], and coinfections by persistent pathogens, including CMV, hepatitis B and C viruses, and Mycobacterium tuberculosis[160,164–167]. Chronic HIV and CMV infections result in senescent T-cells expansion [168], cell surface markers and functions being similar to those of healthy elderly individuals [141,161,169]. However, HIV-related CD8+ senescent phenotype is quite distinct from that observed in ageing, with expansion of well differentiated CD28CD8+ and reduction of CD28CD8+ cells expressing CD57 [170]. Regarding causality, it has been proposed that chronic inflammation associated with HIV disease drives excess activation and proliferation of T cells, which in turn leads to telomere shortening and, ultimately, poor immune recovery and immunosenescence [40]. However, even if adaptive immune activation and immune senescence markers are increased in ageing HIV-infected patients, they fail to predict non-AIDS-defining morbidity and mortality in most studies evaluating these patients, by contrast to markers of innate immune activation and inflammation [97,98].

Environment-related factors

Behavioural risk factors are strongly associated with ageing. Smoking, excessive consumption of alcohol, poor diet, and low levels of physical activity are contributing to half of the burden of age-related illness in developed countries [2]. Alcohol-induced macrophage inflammation enhances hepatocyte senescence [171]. Cigarette smoke is a strong inducer of senescence in lung cells [172,173], strongly associated with chronic lung diseases [174]. Smoking is detrimentally associated with healthy ageing, quality of life, or well-being outcomes. The Mediterranean diet and physical activity are positively associated with healthy and successful ageing, whereas a Western diet (with high intakes of fried and sweet food) is associated with worse outcomes. Drug abuse is also linked to ageing. PBMC from heroin users had lower telomerase activity than healthy controls [175].

Among HIV-infected individuals, deleterious lifestyle factors are frequently observed and associated with enhanced immune activation, smoking, hazardous alcohol consumption, abusing addictive substances, past histories of drug [97,176,177], leading to early ageing and elevated rates of mortality. Most chronic chemical addictions are associated with age-related complications, as neurological and immunological defects and altered metabolic and hepatic biomarkers [178,179]. Alcohol ability to induce liver inflammation might be enhanced in HIV-infected individuals, as well as alcohol-mediated hepatocyte senescence [180]. Smoking is highly prevalent among HIV-infected individuals and associated with enhanced inflammation [181], senescence, and increased mortality [182]. Other lifestyle factors, including obesity and sedentary behavior, shorten life [183].

What biomarkers can be proposed?

To find biomarkers, whether responsible of or associated with ageing, is an important goal for HIV-infected patients. Biomarkers validated in the general population need to be assessed but we also require markers specific to HIV-infected individuals. In addition to ‘universal’ aging markers addressing the biological age, some markers can address specific ageing mechanisms and/or tissue dysfunctions. It is important also to acknowledge that, even if a number of biomarkers are altered in HIV-infected patients, this does not result, at present, in a clear interventional strategy for a given patient.

Genetic and epigenetic markers

We propose to analyze the APOE4 genotype, which was shown to be associated with neurocognitive impairment and with accelerated cognitive decline in HIV-infected patients independently of cholesterol levels [184]. Measures of the epigenetic clock and of the specific hypomethylated status of the HLA region require further validation [33].

Macromolecular damage

Telomere length and telomerase activity are related to ageing and affected by ART. Because of the different replicative potential of different leukocytes, analysis should be performed on purified subpopulations. However, telomere length, considered as a validated biomarker of ageing in the general population, is affected by a number of confounders and technical difficulties with a wide range of variation. In HIV-infected patients, telomere length has not been associated with comorbidities, except an inverse relationship to lung function in patients with chronic obstructive pulmonary disease [185], and therefore could not be recommended at the individual level.

Adaptation to stress

Accumulation of mtDNA mutations represents a useful marker, particularly when performed in highly purified T-cell subsets. Mitochondrial dysfunction could be addressed by quantifying the level of heteroplasmy and the amount of mtDNA.

Markers of oxidative stress can be analyzed both on PBMC and in plasma. Glutathione, superoxide anion, and hydrogen peroxide can be quantified simultaneously inside PBMC, but the analysis needs to be performed rapidly after cell isolation [186]. In plasma, the amount of oxidized forms of metabolites, such as oxidized low density lipoproteins (LDL), carbonylated, or nitrated proteins can represent an indirect but relatively simple measurement of oxidative stress. Importantly, serum oxidized LDL level is elevated in HIV-infected patients, associated with atherosclerosis and decreased in response to statin therapy together with reduced coronary atherosclerosis [187]. This marker appears useful.


It is important to determine which markers could be useful to follow ageing and age-related comorbidities in well controlled HIV-infected patients. The levels of inflammatory markers such as high sensitivity C-reactive protein (hsCRP), IL-6, and D-dimers or of innate immune activation as sCD14 are mildly to moderately increased in infected versus noninfected individuals [181], and generally found associated with comorbidities and mortality, the severity of HIV infection, and/or ART molecules. Their level is also modulated by other factors as age, race, education level, BMI, smoking, hepatitis C virus coinfection [181,188]. hsCRP or D-Dimer, available in the routine care, can be informative for HIV-infected patients’ follow-up, outside of any clinical acute condition. However, there are no clinical interventions showing that decreasing inflammation improved health in these patients. IL-6 or sCD14, evaluating low-grade inflammation and innate immune activation are not routinely performed. Results from the randomized trial to prevent vascular events in HIV REPRIEVE ( NCT02344290) testing whether pitavastatin could decrease atherosclerosis and inflammation are awaited. It would also be important to validate indexes using several markers.

Circulating mtDNA increases with age, and is related to proinflammatory molecules (IL-1β and TNFα), and also increases during HIV infection [189,190]. Thus, mtDNA could become a useful parameter for monitoring inflammation.

Senescence markers can be assessed in PBMC. The validated biomarker of ageing, expression of cyclin dependent kinase inhibitor 2a (CDKN2A), encoding p16INK4a, is increased with age and in HIV-infected patients but can also be affected by smoking and other factors [39,191]. The level of senescence proteins can also be evaluated such as prelamin-A, p16INK4a, p21WAF-1, p53, and activated phospho-p53.


Metabolomics, proteomics, and computational tools have dramatically increased the knowledge of patterns associated with different diseases, at different levels, giving an integrated support for personalized medicine [192,193]. The metabolome, the complete repertoire of small systemic molecules, is studied through metabolome-wide association studies. Metabolomics biomarkers are useful because changes in metabolism can be rapid, and reveal the host physiological status. Metabolomics studies can highlight interactions between inflammation/immune activation and/or senescence and cellular metabolism. In HIV-infected patients receiving protease inhibitor-based ART, metabolomics analysis has revealed that lipid alterations are linked to markers of inflammation, microbial translocation, and hepatic function [194]. In cerebrospinal fluid, the metabolomics profile of young HIV-infected patients presented similarities to that of aged HIV-negative controls, and was associated with worse neurocognitive test scores and plasma inflammatory biomarkers [195]. In oral wash samples, ART-naive individuals presented an increased ratio of phenylalanine/tyrosine associated with immune activation [196]. Metabolomics can also reveal microbiota modifications because some biomarkers could be the end products of microbes’ metabolism. Thus, microbiota-derived metabolites from choline, as trimethylamine and its liver-produced derivative trimethylamine-N-oxide, are markers of cardiovascular risk in HIV-infected patients [197]. In long-term ART-treated patients, HIV infection was associated with defects in metabolites recovered from proline, phenylalanine, and lysine metabolism and accumulation of products of the kynurenine pathway derived from tryptophan metabolism [198]. The serum kynurenine/tryptophan ratio was associated with non-AIDS related outcome and death [98] and with gut dysbiosis [113]. Determination of this ratio should be important for patients’ follow-up [199].

Adaptive immune activation and immune senescence markers

Some age-related markers of adaptive immunity are modified during HIV infection and could be informative in addition to the CD4+:CD8+ ratio: expansion of terminally differentiated CD28 T cells [200–204] and increased frequency of T-cell receptor rearrangement excision circle-positive T cells [146,205,206]. The number of CMV+ T cells could also be monitored, to assess the effect of latent viral infection. Regarding B cells, the analysis the expression of activation-induced cytidine deaminase could be useful to monitor their capability to respond to new antigens, and particularly to vaccines.

Global score of ageing

In the general population, the ‘Biological Age Score’ as determined by the European MARK-AGE consortium uses a set of biomarkers, including the markers resulting from age-modified protein N-glycosylation, combined in an algorithm that would measure biological age (patent method for the determination of biological age in human beings, EP 2976433 A1). In women, these markers are the cumulative level of cytosine methylation at different loci of two genes, ELOVL (elongation of very long chain fatty acids) and FHL2 (four-and-a-half-LIM-only), evaluated in blood cells, together with the serum levels of dehydroepiandrosterone-sulfate (DHAES), ferritin, α-tocopherol, and, regarding the N-glycosylation status of serum proteins, the peak 6 (NA2F) and the log ratio of NGA2F (peak1) and NA2F. In men, in addition to the methylation status of ELOVL and FHL2, and the protein glycan peak 6, plasma levels of DHEAS, α2-macroglobulin, lycopene, and prostate-specific antigen. This algorithm is currently evaluated in the European Coordination Of Biological and chemical information technology Research Activities (COBRA) project. Data presented at the CROI 2017 meeting [207] find that biological age was significantly greater than chronological age by 13.2 years in the HIV-infected group, and by 5.5 years in the non-infected group, with a significant difference between the two groups.

Prospective: what will be our priorities for future research and biomarkers?

Some, but not all, age-related comorbidities have an increased prevalence in ART-treated ageing HIV-infected patients. As well, some mechanisms of ageing are enhanced in these patients and associated with increased morbidity/mortality. This could be the consequence of factors specific to HIV infection, as the virus and some ART, in addition to enhanced classical risk factors. The role of inflammation and innate immune activation in non-AIDS-related comorbidities was well demonstrated, although adaptive immune activation and senescence markers failed to predict mortality, by contrast to the general population. Further studies are required to better understand these dissimilarities.

To evaluate gene expression and proteins in PBMC requires these cells to be separated and prospectively stored, together with serum/plasma samples. It would be important to further identify robust systemic inflammatory and/or immune activation markers or indexes, using several of these markers, to quantify the ageing process in HIV-infected patients. Up to now, these markers, widely used in clinical studies, which were consistently reported to be increased in comorbid HIV-infected patients, have not yet been proven to have clinical utility for patients’ follow-up. The search for biomarkers of ageing will benefit from large-scale approaches as metabolome-wide association studies. Results regarding biological age, analyzed with the MARK-AGE algorithm, need to be pursued in the HIV-infected population.

Owing to the complexity of the ageing process and its multifactorial components, it could be difficult to identify pertinent ‘universal’ biomarkers. We need to search also for more focused biomarkers linked to different mechanisms, tissue dysfunctions, and/or comorbidities.

Animal studies, as simian immunodeficiency virus-infected and treated macaques, or HIV-expressing mouse models, can only partly answer these questions. Such studies will mainly benefit from large cohorts of well paired ageing HIV-infected and noninfected individuals, prospectively followed.

We can expect that data issued from large-scale ‘omics’ approaches obtained in large cohorts will rapidly emerge, to better quantify biological ageing, better predict morbidity and mortality in these patients, and increase their healthspan.


Conflicts of interest

There are no conflicts of interest.


1. Kennedy BK, Berger SL, Brunet A, Campisi J, Cuervo AM, Epel ES, et al. Geroscience: linking aging to chronic disease. Cell 2014; 159:709–713.
2. Lafortune L, Martin S, Kelly S, Kuhn I, Remes O, Cowan A, Brayne C. Behavioural risk factors in mid-life associated with successful ageing, disability, dementia and frailty in later life: a rapid systematic review. PLoS One 2016; 11:e0144405.
3. Pathai S, Bajillan H, Landay AL, High KP. Is HIV a model of accelerated or accentuated aging?. J Gerontol A Biol Sci Med Sci 2014; 69:833–842.
4. Kirkwood TB. A systematic look at an old problem. Nature 2008; 451:644–647.
5. Erol A. Genotoxic stress-mediated cell cycle activities for the decision of cellular fate. Cell Cycle 2011; 10:3239–3248.
6. Burch JB, Augustine AD, Frieden LA, Hadley E, Howcroft TK, Johnson R, et al. Advances in geroscience: impact on healthspan and chronic disease. J Gerontol A Biol Sci Med Sci 2014; 69:S1–S3.
7. Lopez-Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell 2013; 153:1194–1217.
8. Herskind AM, McGue M, Iachine IA, Holm N, Sorensen TI, Harvald B, Vaupel JW. Untangling genetic influences on smoking, body mass index and longevity: a multivariate study of 2464 Danish twins followed for 28 years. Hum Genet 1996; 98:467–475.
9. vB Hjelmborg J, Iachine I, Skytthe A, Vaupel JW, McGue M, Koskenvuo M, et al. Genetic influence on human lifespan and longevity. Hum Genet 2006; 119:312–321.
10. Gavrilova NS, Gavrilov LA, Evdokushkina GN, Semyonova VG, Gavrilova AL, Evdokushkina NN, et al. Evolution, mutations, and human longevity: European royal and noble families. Hum Biol 1998; 70:799–804.
11. Crimmins EM, Finch CE. The genetics of age-related health outcomes. J Gerontol A Biol Sci Med Sci 2012; 67:467–469.
12. Mahley RW, Rall SC Jr. Apolipoprotein E: far more than a lipid transport protein. Annu Rev Genomics Hum Genet 2000; 1:507–537.
13. van der Horst A, Burgering BM. Stressing the role of FoxO proteins in lifespan and disease. Nat Rev Mol Cell Biol 2007; 8:440–450.
14. Nebel A, Kleindorp R, Caliebe A, Nothnagel M, Blanche H, Junge O, et al. A genome-wide association study confirms APOE as the major gene influencing survival in long-lived individuals. Mech Ageing Dev 2011; 132:324–330.
15. Li Y, Wang WJ, Cao H, Lu J, Wu C, Hu FY, et al. Genetic association of FOXO1A and FOXO3A with longevity trait in Han Chinese populations. Hum Mol Genet 2009; 18:4897–4904.
16. Malovini A, Illario M, Iaccarino G, Villa F, Ferrario A, Roncarati R, et al. Association study on long-living individuals from Southern Italy identifies rs10491334 in the CAMKIV gene that regulates survival proteins. Rejuvenation Res 2011; 14:283–291.
17. Newman AB, Walter S, Lunetta KL, Garcia ME, Slagboom PE, Christensen K, et al. A meta-analysis of four genome-wide association studies of survival to age 90 years or older: the cohorts for heart and aging research in genomic epidemiology consortium. J Gerontol A Biol Sci Med Sci 2010; 65:478–487.
18. Walter S, Atzmon G, Demerath EW, Garcia ME, Kaplan RC, Kumari M, et al. A genome-wide association study of aging. Neurobiol Aging 2011; 32:2109e2115–e2128.
19. Wendelken LA, Jahanshad N, Rosen HJ, Busovaca E, Allen I, Coppola G, et al. ApoE ε4 is associated with cognition, brain integrity, and atrophy in HIV over age 60. J Acquir Immune Defic Syndr 2016; 73:426–432.
20. Niemi AK, Moilanen JS, Tanaka M, Hervonen A, Hurme M, Lehtimaki T, et al. A combination of three common inherited mitochondrial DNA polymorphisms promotes longevity in Finnish and Japanese subjects. Eur J Hum Genet 2005; 13:166–170.
21. Tanaka M, Takeyasu T, Fuku N, Li-Jun G, Kurata M. Mitochondrial genome single nucleotide polymorphisms and their phenotypes in the Japanese. Ann N Y Acad Sci 2004; 1011:7–20.
22. De Benedictis G, Rose G, Carrieri G, De Luca M, Falcone E, Passarino G, et al. Mitochondrial DNA inherited variants are associated with successful aging and longevity in humans. FASEB J 1999; 13:1532–1536.
23. Ross OA, McCormack R, Curran MD, Duguid RA, Barnett YA, Rea IM, Middleton B. Mitochondrial DNA polymorphism: its role in longevity of the Irish population. Exp Gerontol 2001; 36:1161–1178.
24. Niemi AK, Hervonen A, Hurme M, Karhunen PJ, Jylha M, Majamaa K. Mitochondrial DNA polymorphisms associated with longevity in a Finnish population. Hum Genet 2003; 112:29–33.
25. Hendrickson SL, Hutcheson HB, Ruiz-Pesini E, Poole JC, Lautenberger J, Sezgin E, et al. Mitochondrial DNA haplogroups influence AIDS progression. AIDS 2008; 22:2429–2439.
26. Grady BJ, Samuels DC, Robbins GK, Selph D, Canter JA, Pollard RB, et al. ACTG 384 and DACS 250 Study Teams. Mitochondrial genomics and CD4 T-cell count recovery after antiretroviral therapy initiation in AIDS clinical trials group study 384. J Acquir Immune Defic Syndr 2011; 58:363–370.
27. Hulgan T, Robbins GK, Kalams SA, Samuels DC, Grady B, Shafer R, et al. AIDS Clinical Trials Group. T cell activation markers and African mitochondrial DNA haplogroups among non-Hispanic black participants in AIDS clinical trials group study 384. PLoS One 2012; 7:e43803.
28. Guzman-Fulgencio M, Jimenez JL, Garcia-Alvarez M, Bellon JM, Fernandez-Rodriguez A, Campos Y, et al. Mitochondrial haplogroups are associated with clinical pattern of AIDS progression in HIV-infected patients. J Acquir Immune Defic Syndr 2013; 63:178–183.
29. Guzman-Fulgencio M, Rallon N, Berenguer J, Fernandez-Rodriguez A, Soriano V, Miralles P, et al. European mitochondrial haplogroups are not associated with hepatitis C virus (HCV) treatment response in HIV/HCV-coinfected patients. HIV Med 2014; 15:425–430.
30. Pal S, Tyler JK. Epigenetics and aging. Sci Adv 2016; 2:e1600584.
31. Sen P, Shah PP, Nativio R, Berger SL. Epigenetic mechanisms of longevity and aging. Cell 2016; 166:822–839.
32. Horvath S. DNA methylation age of human tissues and cell types. Genome Biol 2013; 14:R115.
33. Gross AM, Jaeger PA, Kreisberg JF, Licon K, Jepsen KL, Khosroheidari M, et al. Methylome-wide analysis of chronic HIV infection reveals five-year increase in biological age and epigenetic targeting of HLA. Mol Cell 2016; 62:157–168.
34. Richardson AG, Schadt EE. The role of macromolecular damage in aging and age-related disease. J Gerontol A Biol Sci Med Sci 2014; 69:S28–S32.
35. Moskalev AA, Shaposhnikov MV, Plyusnina EN, Zhavoronkov A, Budovsky A, Yanai H, Fraifeld VE. The role of DNA damage and repair in aging through the prism of Koch-like criteria. Ageing Res Rev 2013; 12:661–684.
36. Shammas MA. Telomeres, lifestyle, cancer, and aging. Curr Opin Clin Nutr Metab Care 2011; 14:28–34.
37. Babizhayev MA, Savel’yeva EL, Moskvina SN, Yegorov YE. Telomere length is a biomarker of cumulative oxidative stress, biologic age, and an independent predictor of survival and therapeutic treatment requirement associated with smoking behavior. Am J Ther 2011; 18:e209–e226.
38. Cawthon RM, Smith KR, O’Brien E, Sivatchenko A, Kerber RA. Association between telomere length in blood and mortality in people aged 60 years or older. Lancet 2003; 361:393–395.
39. Pathai S, Lawn SD, Gilbert CE, McGuinness D, McGlynn L, Weiss HA, et al. Accelerated biological ageing in HIV-infected individuals in South Africa: a case-control study. AIDS 2013; 27:2375–2384.
40. Cobos Jimenez V, Wit FW, Joerink M, Maurer I, Harskamp AM, Schouten J, et al. AGEhIV Study Group. T-cell activation independently associates with immune senescence in HIV-infected recipients of long-term antiretroviral treatment. J Infect Dis 2016; 214:216–225.
41. Hukezalie KR, Thumati NR, Cote HC, Wong JM. In vitro and ex vivo inhibition of human telomerase by anti-HIV nucleoside reverse transcriptase inhibitors (NRTIs) but not by non-NRTIs. PLoS One 2012; 7:e47505.
42. Leeansyah E, Cameron PU, Solomon A, Tennakoon S, Velayudham P, Gouillou M, et al. Inhibition of telomerase activity by human immunodeficiency virus (HIV) nucleos(t)ide reverse transcriptase inhibitors: a potential factor contributing to HIV-associated accelerated aging. J Infect Dis 2013; 207:1157–1165.
43. Simonetti S, Chen X, DiMauro S, Schon EA. Accumulation of deletions in human mitochondrial DNA during normal aging: analysis by quantitative PCR. Biochim Biophys Acta 1992; 1180:113–122.
44. Bua E, Johnson J, Herbst A, Delong B, McKenzie D, Salamat S, Aiken JM. Mitochondrial DNA-deletion mutations accumulate intracellularly to detrimental levels in aged human skeletal muscle fibers. Am J Hum Genet 2006; 79:469–480.
45. Wang Y, Michikawa Y, Mallidis C, Bai Y, Woodhouse L, Yarasheski KE, et al. Muscle-specific mutations accumulate with aging in critical human mtDNA control sites for replication. Proc Natl Acad Sci U S A 2001; 98:4022–4027.
46. Corral-Debrinski M, Horton T, Lott MT, Shoffner JM, Beal MF, Wallace DC. Mitochondrial DNA deletions in human brain: regional variability and increase with advanced age. Nat Genet 1992; 2:324–329.
47. Tocchi A, Quarles EK, Basisty N, Gitari L, Rabinovitch PS. Mitochondrial dysfunction in cardiac aging. Biochim Biophys Acta 2015; 1847:1424–1433.
48. Garrido N, Griparic L, Jokitalo E, Wartiovaara J, van der Bliek AM, Spelbrink JN. Composition and dynamics of human mitochondrial nucleoids. Mol Biol Cell 2003; 14:1583–1596.
49. Pinto M, Moraes CT. Mechanisms linking mtDNA damage and aging. Free Radic Biol Med 2015; 85:250–258.
50. Wanagat J, Cao Z, Pathare P, Aiken JM. Mitochondrial DNA deletion mutations colocalize with segmental electron transport system abnormalities, muscle fiber atrophy, fiber splitting, and oxidative damage in sarcopenia. FASEB J 2001; 15:322–332.
51. Macho A, Castedo M, Marchetti P, Aguilar JJ, Decaudin D, Zamzami N, et al. Mitochondrial dysfunctions in circulating T lymphocytes from human immunodeficiency virus-1 carriers. Blood 1995; 86:2481–2487.
52. Gil L, Martinez G, Gonzalez I, Tarinas A, Alvarez A, Giuliani A, et al. Contribution to characterization of oxidative stress in HIV/AIDS patients. Pharmacol Res 2003; 47:217–224.
53. Ladha JS, Tripathy MK, Mitra D. Mitochondrial complex I activity is impaired during HIV-1-induced T-cell apoptosis. Cell Death Differ 2005; 12:1417–1428.
54. Maagaard A, Holberg-Petersen M, Kvittingen EA, Sandvik L, Bruun JN. Depletion of mitochondrial DNA copies/cell in peripheral blood mononuclear cells in HIV-1-infected treatment-naive patients. HIV Med 2006; 7:53–58.
55. Miura T, Goto M, Hosoya N, Odawara T, Kitamura Y, Nakamura T, Iwamoto A. Depletion of mitochondrial DNA in HIV-1-infected patients and its amelioration by antiretroviral therapy. J Med Virol 2003; 70:497–505.
56. Pinti M, Salomoni P, Cossarizza A. Anti-HIV drugs and the mitochondria. Biochim Biophys Acta 2006; 1757:700–707.
57. Warner HR. Is cell death and replacement a factor in aging?. Mech Ageing Dev 2007; 128:13–16.
58. Franceschi V, Parker S, Jacca S, Crump RW, Doronin K, Hembrador E, et al. BoHV-4-based vector single heterologous antigen delivery protects STAT1(-/-) mice from monkeypoxvirus lethal challenge. PLoS Negl Trop Dis 2015; 9:e0003850.
59. Ginaldi L, De Martinis M, Monti D, Franceschi C. Chronic antigenic load and apoptosis in immunosenescence. Trends Immunol 2005; 26:79–84.
60. Monti D, Salvioli S, Capri M, Malorni W, Straface E, Cossarizza A, et al. Decreased susceptibility to oxidative stress-induced apoptosis of peripheral blood mononuclear cells from healthy elderly and centenarians. Mech Ageing Dev 2000; 121:239–250.
61. Aggarwal S, Gupta S. Increased apoptosis of T cell subsets in aging humans: altered expression of Fas (CD95), Fas ligand, Bcl-2, and Bax. J Immunol 1998; 160:1627–1637.
62. Aggarwal S, Gollapudi S, Gupta S. Increased TNF-alpha-induced apoptosis in lymphocytes from aged humans: changes in TNF-alpha receptor expression and activation of caspases. J Immunol 1999; 162:2154–2161.
63. Fagnoni FF, Vescovini R, Passeri G, Bologna G, Pedrazzoni M, Lavagetto G, et al. Shortage of circulating naive CD8(+) T cells provides new insights on immunodeficiency in aging. Blood 2000; 95:2860–2868.
64. Miura Y, Koyanagi Y. Death ligand-mediated apoptosis in HIV infection. Rev Med Virol 2005; 15:169–178.
65. Westendorp MO, Frank R, Ochsenbauer C, Stricker K, Dhein J, Walczak H, et al. Sensitization of T cells to CD95-mediated apoptosis by HIV-1 Tat and gp120. Nature 1995; 375:497–500.
66. Zhang M, Li X, Pang X, Ding L, Wood O, Clouse K, et al. Identification of a potential HIV-induced source of bystander-mediated apoptosis in T cells: upregulation of trail in primary human macrophages by HIV-1 tat. J Biomed Sci 2001; 8:290–296.
67. Lum JJ, Schnepple DJ, Badley AD. Acquired T-cell sensitivity to TRAIL mediated killing during HIV infection is regulated by CXCR4-gp120 interactions. AIDS 2005; 19:1125–1133.
68. Muthumani K, Choo AY, Hwang DS, Premkumar A, Dayes NS, Harris C, et al. HIV-1 Nef-induced FasL induction and bystander killing requires p38 MAPK activation. Blood 2005; 106:2059–2068.
69. Cossarizza A. Apoptosis and HIV infection: about molecules and genes. Curr Pharm Des 2008; 14:237–244.
70. Yang Z, Klionsky DJ. Eaten alive: a history of macroautophagy. Nat Cell Biol 2010; 12:814–822.
71. Levine B, Kroemer G. Autophagy in aging, disease and death: the true identity of a cell death impostor. Cell Death Differ 2009; 16:1–2.
72. Matsui A, Kamada Y, Matsuura A. The role of autophagy in genome stability through suppression of abnormal mitosis under starvation. PLoS Genet 2013; 9:e1003245.
73. Simonsen A, Cumming RC, Brech A, Isakson P, Schubert DR, Finley KD. Promoting basal levels of autophagy in the nervous system enhances longevity and oxidant resistance in adult Drosophila. Autophagy 2008; 4:176–184.
74. Pyo JO, Yoo SM, Ahn HH, Nah J, Hong SH, Kam TI, et al. Overexpression of Atg5 in mice activates autophagy and extends lifespan. Nat Commun 2013; 4:2300.
75. Taneike M, Yamaguchi O, Nakai A, Hikoso S, Takeda T, Mizote I, et al. Inhibition of autophagy in the heart induces age-related cardiomyopathy. Autophagy 2010; 6:600–606.
76. Lipinski MM, Zheng B, Lu T, Yan Z, Py BF, Ng A, et al. Genome-wide analysis reveals mechanisms modulating autophagy in normal brain aging and in Alzheimer's disease. Proc Natl Acad Sci U S A 2010; 107:14164–14169.
77. Nixon RA, Wegiel J, Kumar A, Yu WH, Peterhoff C, Cataldo A, Cuervo AM. Extensive involvement of autophagy in Alzheimer disease: an immuno-electron microscopy study. J Neuropathol Exp Neurol 2005; 64:113–122.
78. Crews L, Spencer B, Desplats P, Patrick C, Paulino A, Rockenstein E, et al. Selective molecular alterations in the autophagy pathway in patients with Lewy body disease and in models of alpha-synucleinopathy. PLoS One 2010; 5:e9313.
79. Hirota Y, Kang D, Kanki T. The physiological role of mitophagy: new insights into phosphorylation events. Int J Cell Biol 2012; 2012:354914.
80. Sgarbi G, Matarrese P, Pinti M, Lanzarini C, Ascione B, Gibellini L, et al. Mitochondria hyperfusion and elevated autophagic activity are key mechanisms for cellular bioenergetic preservation in centenarians. Aging (Albany NY) 2014; 6:296–310.
81. Fields J, Dumaop W, Eleuteri S, Campos S, Serger E, Trejo M, et al. HIV-1 Tat alters neuronal autophagy by modulating autophagosome fusion to the lysosome: implications for HIV-associated neurocognitive disorders. J Neurosci 2015; 35:1921–1938.
82. Alirezaei M, Kiosses WB, Fox HS. Decreased neuronal autophagy in HIV dementia: a mechanism of indirect neurotoxicity. Autophagy 2008; 4:963–966.
83. Zhou D, Masliah E, Spector SA. Autophagy is increased in postmortem brains of persons with HIV-1-associated encephalitis. J Infect Dis 2011; 203:1647–1657.
84. Fields J, Dumaop W, Rockenstein E, Mante M, Spencer B, Grant I, et al. Age-dependent molecular alterations in the autophagy pathway in HIVE patients and in a gp120 tg mouse model: reversal with beclin-1 gene transfer. J Neurovirol 2013; 19:89–101.
85. Beaupere C, Garcia M, Larghero J, Feve B, Capeau J, Lagathu C. The HIV proteins Tat and Nef promote human bone marrow mesenchymal stem cell senescence and alter osteoblastic differentiation. Aging Cell 2015; 14:534–546.
86. Maharjan S, Oku M, Tsuda M, Hoseki J, Sakai Y. Mitochondrial impairment triggers cytosolic oxidative stress and cell death following proteasome inhibition. Sci Rep 2014; 4:5896.
87. Pinti M, Gibellini L, Liu Y, Xu S, Lu B, Cossarizza A. Mitochondrial Lon protease at the crossroads of oxidative stress, ageing and cancer. Cell Mol Life Sci 2015; 72:4807–4824.
88. Taylor RC. Aging and the UPR(ER). Brain Res 2016; 1648:588–593.
89. Norman JP, Perry SW, Reynolds HM, Kiebala M, De Mesy Bentley KL, Trejo M, et al. HIV-1 Tat activates neuronal ryanodine receptors with rapid induction of the unfolded protein response and mitochondrial hyperpolarization. PLoS One 2008; 3:e3731.
90. Zhou H, Gurley EC, Jarujaron S, Ding H, Fang Y, Xu Z, et al. HIV protease inhibitors activate the unfolded protein response and disrupt lipid metabolism in primary hepatocytes. Am J Physiol Gastrointest Liver Physiol 2006; 291:G1071–G1080.
91. Zhou H, Pandak WM Jr, Lyall V, Natarajan R, Hylemon PB. HIV protease inhibitors activate the unfolded protein response in macrophages: implication for atherosclerosis and cardiovascular disease. Mol Pharmacol 2005; 68:690–700.
92. Chen L, Jarujaron S, Wu X, Sun L, Zha W, Liang G, et al. HIV protease inhibitor lopinavir-induced TNF-alpha and IL-6 expression is coupled to the unfolded protein response and ERK signaling pathways in macrophages. Biochem Pharmacol 2009; 78:70–77.
93. Wu X, Sun L, Zha W, Studer E, Gurley E, Chen L, et al. HIV protease inhibitors induce endoplasmic reticulum stress and disrupt barrier integrity in intestinal epithelial cells. Gastroenterology 2010; 138:197–209.
94. Apostolova N, Gomez-Sucerquia LJ, Alegre F, Funes HA, Victor VM, Barrachina MD, et al. ER stress in human hepatic cells treated with Efavirenz: mitochondria again. J Hepatol 2013; 59:780–789.
95. Franceschi C, Campisi J. Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. J Gerontol A Biol Sci Med Sci 2014; 69 (Suppl 1):S4–S9.
96. Fabbri E, An Y, Zoli M, Simonsick EM, Guralnik JM, Bandinelli S, et al. Aging and the burden of multimorbidity: associations with inflammatory and anabolic hormonal biomarkers. J Gerontol A Biol Sci Med Sci 2015; 70:63–70.
97. Hunt PW, Lee SA, Siedner MJ. Immunologic biomarkers, morbidity, and mortality in treated HIV infection. J Infect Dis 2016; 214 (Suppl 2):S44–S50.
98. Tenorio AR, Zheng Y, Bosch RJ, Krishnan S, Rodriguez B, Hunt PW, et al. Soluble markers of inflammation and coagulation but not T-cell activation predict non-AIDS-defining morbid events during suppressive antiretroviral treatment. J Infect Dis 2014; 210:1248–1259.
99. Nordell AD, McKenna M, Borges AH, Duprez D, Neuhaus J, Neaton JD. INSIGHT SMART, ESPRIT Study Groups; SILCAAT Scientific Committee. Severity of cardiovascular disease outcomes among patients with HIV is related to markers of inflammation and coagulation. J Am Heart Assoc 2014; 3:e000844.
100. Youm YH, Grant RW, McCabe LR, Albarado DC, Nguyen KY, Ravussin A, et al. Canonical Nlrp3 inflammasome links systemic low-grade inflammation to functional decline in aging. Cell Metab 2013; 18:519–532.
101. Goldberg EL, Dixit VD. Drivers of age-related inflammation and strategies for healthspan extension. Immunol Rev 2015; 265:63–74.
102. Nasi M, De Biasi S, Bianchini E, Digaetano M, Pinti M, Gibellini L, et al. Analysis of inflammasomes and antiviral sensing components reveals decreased expression of NLRX1 in HIV-positive patients assuming efficient antiretroviral therapy. AIDS 2015; 29:1937–1941.
103. van Deursen JM. The role of senescent cells in ageing. Nature 2014; 509:439–446.
104. Baker DJ, Childs BG, Durik M, Wijers ME, Sieben CJ, Zhong J, et al. Naturally occurring p16(Ink4a)-positive cells shorten healthy lifespan. Nature 2016; 530:184–189.
105. Gonzalo S, Kreienkamp R, Askjaer P. Hutchinson-Gilford progeria syndrome: a premature aging disease caused by LMNA gene mutations. Ageing Res Rev 2017; 33:18–29.
106. Caron M, Auclair M, Donadille B, Bereziat V, Guerci B, Laville M, et al. Human lipodystrophies linked to mutations in A-type lamins and to HIV protease inhibitor therapy are both associated with prelamin A accumulation, oxidative stress and premature cellular senescence. Cell Death Differ 2007; 14:1759–1767.
107. Hernandez-Vallejo SJ, Beaupere C, Larghero J, Capeau J, Lagathu C. HIV protease inhibitors induce senescence and alter osteoblastic potential of human bone marrow mesenchymal stem cells: beneficial effect of pravastatin. Aging Cell 2013; 12:955–965.
108. Caron M, Auclair M, Vissian A, Vigouroux C, Capeau J. Contribution of mitochondrial dysfunction and oxidative stress to cellular premature senescence induced by antiretroviral thymidine analogues. Antivir Ther 2008; 13:27–38.
109. Afonso P, Auclair M, Boccara F, Vantyghem MC, Katlama C, Capeau J, et al. LMNA mutations resulting in lipodystrophy and HIV protease inhibitors trigger vascular smooth muscle cell senescence and calcification: role of ZMPSTE24 downregulation. Atherosclerosis 2016; 245:200–211.
110. Auclair M, Afonso P, Capel E, Caron-Debarle M, Capeau J. Impact of darunavir, atazanavir and lopinavir boosted with ritonavir on cultured human endothelial cells: beneficial effect of pravastatin. Antivir Ther 2014; 19:773–782.
111. Nikoletopoulou V, Kyriakakis E, Tavernarakis N. Cellular and molecular longevity pathways: the old and the new. Trends Endocrinol Metab 2014; 25:212–223.
112. Biagi E, Nylund L, Candela M, Ostan R, Bucci L, Pini E, et al. Through ageing, and beyond: gut microbiota and inflammatory status in seniors and centenarians. PLoS One 2010; 5:e10667.
113. Vujkovic-Cvijin I, Dunham RM, Iwai S, Maher MC, Albright RG, Broadhurst MJ, et al. Dysbiosis of the gut microbiota is associated with HIV disease progression and tryptophan catabolism. Sci Transl Med 2013; 5: 193ra191.
114. Dillon SM, Lee EJ, Kotter CV, Austin GL, Dong Z, Hecht DK, et al. An altered intestinal mucosal microbiome in HIV-1 infection is associated with mucosal and systemic immune activation and endotoxemia. Mucosal Immunol 2014; 7:983–994.
115. Zevin AS, McKinnon L, Burgener A, Klatt NR. Microbial translocation and microbiome dysbiosis in HIV-associated immune activation. Curr Opin HIV AIDS 2016; 11:182–190.
116. Mudd JC, Brenchley JM. Gut mucosal barrier dysfunction, microbial dysbiosis, and their role in HIV-1 disease progression. J Infect Dis 2016; 214 (Suppl 2):S58–S66.
117. Hunt PW, Sinclair E, Rodriguez B, Shive C, Clagett B, Funderburg N, et al. Gut epithelial barrier dysfunction and innate immune activation predict mortality in treated HIV infection. J Infect Dis 2014; 210:1228–1238.
118. de Araujo AL, Silva LC, Fernandes JR, Benard G. Preventing or reversing immunosenescence: can exercise be an immunotherapy?. Immunotherapy 2013; 5:879–893.
119. Newgard CB, Pessin JE. Recent progress in metabolic signaling pathways regulating aging and life span. J Gerontol A Biol Sci Med Sci 2014; 69 (Suppl 1):S21–S27.
120. Araujo S, Banon S, Machuca I, Moreno A, Perez-Elias MJ, Casado JL. Prevalence of insulin resistance and risk of diabetes mellitus in HIV-infected patients receiving current antiretroviral drugs. Eur J Endocrinol 2014; 171:545–554.
121. Rochira V, Diazzi C, Santi D, Brigante G, Ansaloni A, Decaroli MC, et al. Low testosterone is associated with poor health status in men with human immunodeficiency virus infection: a retrospective study. Andrology 2015; 3:298–308.
122. Stanley TL, Grinspoon SK. GH/GHRH axis in HIV lipodystrophy. Pituitary 2009; 12:143–152.
123. Guo Z, Hensrud DD, Johnson CM, Jensen MD. Regional postprandial fatty acid metabolism in different obesity phenotypes. Diabetes 1999; 48:1586–1592.
124. Lutz W, Sanderson W, Scherbov S. The coming acceleration of global population ageing. Nature 2008; 451:716–719.
125. Wu D, Ren Z, Pae M, Guo W, Cui X, Merrill AH, Meydani SN. Aging up-regulates expression of inflammatory mediators in mouse adipose tissue. J Immunol 2007; 179:4829–4839.
126. Newsholme P, de Bittencourt PI Jr. The fat cell senescence hypothesis: a mechanism responsible for abrogating the resolution of inflammation in chronic disease. Curr Opin Clin Nutr Metab Care 2014; 17:295–305.
127. Caron-Debarle M, Lagathu C, Boccara F, Vigouroux C, Capeau J. HIV-associated lipodystrophy: from fat injury to premature aging. Trends Mol Med 2010; 16:218–229.
128. Koethe JR, Hulgan T, Niswender K. Adipose tissue and immune function: a review of evidence relevant to HIV infection. J Infect Dis 2013; 208:1194–1201.
129. van Zoest RA, Wit FW, Kooij KW, van der Valk M, Schouten J, Kootstra NA, et al. AGEhIV Cohort Study Group. Higher prevalence of hypertension in HIV-1-infected patients on combination antiretroviral therapy is associated with changes in body composition and prior stavudine exposure. Clin Infect Dis 2016; 63:205–213.
130. Couturier J, Suliburk JW, Brown JM, Luke DJ, Agarwal N, Yu X, et al. Human adipose tissue as a reservoir for memory CD4+ T cells and HIV. AIDS 2015; 29:667–674.
131. Damouche A, Lazure T, Avettand-Fenoel V, Huot N, Dejucq-Rainsford N, Satie AP, et al. Adipose tissue is a neglected viral reservoir and an inflammatory site during chronic HIV and SIV infection. PLoS Pathog 2015; 11:e1005153.
132. Gallego-Escuredo JM, Villarroya J, Domingo P, Targarona EM, Alegre M, Domingo JC, et al. Differentially altered molecular signature of visceral adipose tissue in HIV-1-associated lipodystrophy. J Acquir Immune Defic Syndr 2013; 64:142–148.
133. Diaz-Delfin J, Domingo P, Wabitsch M, Giralt M, Villarroya F. HIV-1 Tat protein impairs adipogenesis and induces the expression and secretion of proinflammatory cytokines in human SGBS adipocytes. Antivir Ther 2012; 17:529–540.
134. Otake K, Omoto S, Yamamoto T, Okuyama H, Okada H, Okada N, et al. HIV-1 Nef protein in the nucleus influences adipogenesis as well as viral transcription through the peroxisome proliferator-activated receptors. AIDS 2004; 18:189–198.
135. Agarwal N, Iyer D, Patel SG, Sekhar RV, Phillips TM, Schubert U, et al. HIV-1 Vpr induces adipose dysfunction in vivo through reciprocal effects on PPAR/GR co-regulation. Sci Transl Med 2013; 5: 213ra164.
136. Shrivastav S, Kino T, Cunningham T, Ichijo T, Schubert U, Heinklein P, et al. Human immunodeficiency virus (HIV)-1 viral protein R suppresses transcriptional activity of peroxisome proliferator-activated receptor {gamma} and inhibits adipocyte differentiation: implications for HIV-associated lipodystrophy. Mol Endocrinol 2008; 22:234–247.
137. Lefevre C, Auclair M, Boccara F, Bastard JP, Capeau J, Vigouroux C, Caron-Debarle M. Premature senescence of vascular cells is induced by HIV protease inhibitors: implication of prelamin A and reversion by statin. Arterioscler Thromb Vasc Biol 2010; 30:2611–2620.
138. Bereziat V, Cervera P, Le Dour C, Verpont MC, Dumont S, Vantyghem MC, et al. Lipodystrophy Study Group. LMNA mutations induce a non-inflammatory fibrosis and a brown fat-like dystrophy of enlarged cervical adipose tissue. Am J Pathol 2011; 179:2443–2453.
139. Mansilla E, Diaz Aquino V, Zambon D, Marin GH, Martire K, Roque G, et al. Could metabolic syndrome, lipodystrophy, and aging be mesenchymal stem cell exhaustion syndromes?. Stem Cells Int 2011; 2011:943216.
140. Rando TA, Wyss-Coray T. Stem cells as vehicles for youthful regeneration of aged tissues. J Gerontol A Biol Sci Med Sci 2014; 69 (Suppl 1):S39–S42.
141. Pinti M, Appay V, Campisi J, Frasca D, Fulop T, Sauce D, et al. Aging of the immune system: focus on inflammation and vaccination. Eur J Immunol 2016; 46:2286–2301.
142. Shaw AC, Goldstein DR, Montgomery RR. Age-dependent dysregulation of innate immunity. Nat Rev Immunol 2013; 13:875–887.
143. Sansoni P, Cossarizza A, Brianti V, Fagnoni F, Snelli G, Monti D, et al. Lymphocyte subsets and natural killer cell activity in healthy old people and centenarians. Blood 1993; 82:2767–2773.
144. Camous X, Pera A, Solana R, Larbi A. NK cells in healthy aging and age-associated diseases. J Biomed Biotechnol 2012; 2012:195956.
145. Pinti M, Nasi M, Lugli E, Gibellini L, Bertoncelli L, Roat E, et al. T cell homeostasis in centenarians: from the thymus to the periphery. Curr Pharm Des 2010; 16:597–603.
146. Nasi M, Troiano L, Lugli E, Pinti M, Ferraresi R, Monterastelli E, et al. Thymic output and functionality of the IL-7/IL-7 receptor system in centenarians: implications for the neolymphogenesis at the limit of human life. Aging Cell 2006; 5:167–175.
147. Lugli E, Pinti M, Nasi M, Troiano L, Ferraresi R, Mussi C, et al. Subject classification obtained by cluster analysis and principal component analysis applied to flow cytometric data. Cytometry A 2007; 71:334–344.
148. Henson SM, Lanna A, Riddell NE, Franzese O, Macaulay R, Griffiths SJ, et al. p38 signaling inhibits mTORC1-independent autophagy in senescent human CD8+ T cells. J Clin Invest 2014; 124:4004–4016.
149. Henson SM, Macaulay R, Riddell NE, Nunn CJ, Akbar AN. Blockade of PD-1 or p38 MAP kinase signaling enhances senescent human CD8(+) T-cell proliferation by distinct pathways. Eur J Immunol 2015; 45:1441–1451.
150. Derhovanessian E, Chen S, Maier AB, Hahnel K, de Craen AJ, Roelofs H, et al. CCR4+ regulatory T cells accumulate in the very elderly and correlate with superior 8-year survival. J Gerontol A Biol Sci Med Sci 2015; 70:917–923.
151. Strindhall J, Skog M, Ernerudh J, Bengner M, Lofgren S, Matussek A, et al. The inverted CD4/CD8 ratio and associated parameters in 66-year-old individuals: the Swedish HEXA immune study. Age (Dordr) 2013; 35:985–991.
152. Muller GC, Gottlieb MG, Luz Correa B, Gomes Filho I, Moresco RN, Bauer ME. The inverted CD4:CD8 ratio is associated with gender-related changes in oxidative stress during aging. Cell Immunol 2015; 296:149–154.
153. Effros RB, Dagarag M, Spaulding C, Man J. The role of CD8+ T-cell replicative senescence in human aging. Immunol Rev 2005; 205:147–157.
154. Vallejo AN. CD28 extinction in human T cells: altered functions and the program of T-cell senescence. Immunol Rev 2005; 205:158–169.
155. Vescovini R, Telera A, Fagnoni FF, Biasini C, Medici MC, Valcavi P, et al. Different contribution of EBV and CMV infections in very long-term carriers to age-related alterations of CD8+ T cells. Exp Gerontol 2004; 39:1233–1243.
156. Tabibian-Keissar H, Hazanov L, Schiby G, Rosenthal N, Rakovsky A, Michaeli M, et al. Aging affects B-cell antigen receptor repertoire diversity in primary and secondary lymphoid tissues. Eur J Immunol 2016; 46:480–492.
157. Khurana S, Frasca D, Blomberg B, Golding H. AID activity in B cells strongly correlates with polyclonal antibody affinity maturation in-vivo following pandemic 2009-H1N1 vaccination in humans. PLoS Pathog 2012; 8:e1002920.
158. Frasca D, Landin AM, Lechner SC, Ryan JG, Schwartz R, Riley RL, Blomberg BB. Aging down-regulates the transcription factor E2A, activation-induced cytidine deaminase, and Ig class switch in human B cells. J Immunol 2008; 180:5283–5290.
159. Frasca D, Diaz A, Romero M, Landin AM, Phillips M, Lechner SC, et al. Intrinsic defects in B cell response to seasonal influenza vaccination in elderly humans. Vaccine 2010; 28:8077–8084.
160. Nasi M, Pinti M, Mussini C, Cossarizza A. Persistent inflammation in HIV infection: established concepts, new perspectives. Immunol Lett 2014; 161:184–188.
161. Appay V, Almeida JR, Sauce D, Autran B, Papagno L. Accelerated immune senescence and HIV-1 infection. Exp Gerontol 2007; 42:432–437.
162. Brenchley JM, Price DA, Schacker TW, Asher TE, Silvestri G, Rao S, et al. Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat Med 2006; 12:1365–1371.
163. Ryscavage P, Kelly S, Li JZ, Harrigan PR, Taiwo B. Significance and clinical management of persistent low-level viremia and very-low-level viremia in HIV-1-infected patients. Antimicrob Agents Chemother 2014; 58:3585–3598.
164. Nakanjako D, Kiragga AN, Castelnuovo B, Kyabayinze DJ, Kamya MR. Low prevalence of Plasmodium falciparum antigenaemia among asymptomatic HAART-treated adults in an urban cohort in Uganda. Malar J 2011; 10:66.
165. Feuth T, Arends JE, Fransen JH, Nanlohy NM, van Erpecum KJ, Siersema PD, et al. Complementary role of HCV and HIV in T-cell activation and exhaustion in HIV/HCV coinfection. PLoS One 2013; 8:e59302.
166. Chou JP, Ramirez CM, Wu JE, Effros RB. Accelerated aging in HIV/AIDS: novel biomarkers of senescent human CD8+ T cells. PLoS One 2013; 8:e64702.
167. Nasi M, De Biasi S, Gibellini L, Bianchini E, Pecorini S, Bacca V, et al. Ageing and inflammation in patients with HIV infection. Clin Exp Immunol 2017; 187:44–52.
168. Shankar EM, Velu V, Kamarulzaman A, Larsson M. Mechanistic insights on immunosenescence and chronic immune activation in HIV-tuberculosis co-infection. World J Virol 2015; 4:17–24.
169. Deeks SG, Phillips AN. HIV infection, antiretroviral treatment, ageing, and non-AIDS related morbidity. BMJ 2009; 338:a3172.
170. Lee SA, Sinclair E, Hatano H, Hsue PY, Epling L, Hecht FM, et al. Impact of HIV on CD8+ T cell CD57 expression is distinct from that of CMV and aging. PLoS One 2014; 9:e89444.
171. Wan J, Benkdane M, Alons E, Lotersztajn S, Pavoine C. M2 kupffer cells promote hepatocyte senescence: an IL-6-dependent protective mechanism against alcoholic liver disease. Am J Pathol 2014; 184:1763–1772.
172. Ahmad T, Sundar IK, Lerner CA, Gerloff J, Tormos AM, Yao H, Rahman I. Impaired mitophagy leads to cigarette smoke stress-induced cellular senescence: implications for chronic obstructive pulmonary disease. FASEB J 2015; 29:2912–2929.
173. Nyunoya T, Mebratu Y, Contreras A, Delgado M, Chand HS, Tesfaigzi Y. Molecular processes that drive cigarette smoke-induced epithelial cell fate of the lung. Am J Respir Cell Mol Biol 2014; 50:471–482.
174. Adnot S, Amsellem V, Boyer L, Marcos E, Saker M, Houssaini A, et al. Telomere dysfunction and cell senescence in chronic lung diseases: therapeutic potential. Pharmacol Ther 2015; 153:125–134.
175. Cheng GL, Zeng H, Leung MK, Zhang HJ, Lau BW, Liu YP, et al. Heroin abuse accelerates biological aging: a novel insight from telomerase and brain imaging interaction. Transl Psychiatry 2013; 3:e260.
176. Durvasula R, Miller TR. Substance abuse treatment in persons with HIV/AIDS: challenges in managing triple diagnosis. Behav Med 2014; 40:43–52.
177. Murrill CS, Prevots DR, Miller MS, Linley LA, Royalty JE, Gwinn M. Seroincidence Study Group. Incidence of HIV among injection drug users entering drug treatment programs in four US cities. J Urban Health 2001; 78:152–161.
178. Tiwari S, Nair MP, Saxena SK. Latest trends in drugs of abuse – HIV infection and neuroAIDS. Future Virol 2013; 8:121–127.
179. Reece AS. Evidence of accelerated ageing in clinical drug addiction from immune, hepatic and metabolic biomarkers. Immun Ageing 2007; 4:6.
180. Sued O, Figueroa MI, Cahn P. Clinical challenges in HIV/AIDS: hints for advancing prevention and patient management strategies. Adv Drug Deliv Rev 2016; 103:5–19.
181. Bastard JP, Fellahi S, Couffignal C, Raffi F, Gras G, Hardel L, et al. ANRS CO8 APROCO-COPILOTE Cohort Study Group. Increased systemic immune activation and inflammatory profile of long-term HIV-infected ART-controlled patients is related to personal factors, but not to markers of HIV infection severity. J Antimicrob Chemother 2015; 70:1816–1824.
182. Helleberg M, Afzal S, Kronborg G, Larsen CS, Pedersen G, Pedersen C, et al. Mortality attributable to smoking among HIV-1-infected individuals: a nationwide, population-based cohort study. Clin Infect Dis 2013; 56:727–734.
183. Rizzuto D, Fratiglioni L. Lifestyle factors related to mortality and survival: a mini-review. Gerontology 2014; 60:327–335.
184. Mukerji SS, Locascio JJ, Misra V, Lorenz DR, Holman A, Dutta A, et al. Lipid profiles and APOE4 allele impact midlife cognitive decline in HIV-infected men on antiretroviral therapy. Clin Infect Dis 2016; 63:1130–1139.
185. Liu JC, Leung JM, Ngan DA, Nashta NF, Guillemi S, Harris M, et al. Absolute leukocyte telomere length in HIV-infected and uninfected individuals: evidence of accelerated cell senescence in HIV-associated chronic obstructive pulmonary disease. PLoS One 2015; 10:e0124426.
186. Cossarizza A, Ferraresi R, Troiano L, Roat E, Gibellini L, Bertoncelli L, et al. Simultaneous analysis of reactive oxygen species and reduced glutathione content in living cells by polychromatic flow cytometry. Nat Protoc 2009; 4:1790–1797.
187. Nou E, Lu MT, Looby SE, Fitch KV, Kim EA, Lee H, et al. Serum oxidized low-density lipoprotein decreases in response to statin therapy and relates independently to reductions in coronary plaque in patients with HIV. AIDS 2016; 30:583–590.
188. Borges AH, O’Connor JL, Phillips AN, Ronsholt FF, Pett S, Vjecha MJ, et al. INSIGHT SMART and ESPRIT Study Groups and the SILCAAT Scientific Committee. Factors associated with plasma IL-6 levels during HIV infection. J Infect Dis 2015; 212:585–595.
189. Cossarizza A, Pinti M, Nasi M, Gibellini L, Manzini S, Roat E, et al. Increased plasma levels of extracellular mitochondrial DNA during HIV infection: a new role for mitochondrial damage-associated molecular patterns during inflammation. Mitochondrion 2011; 11:750–755.
190. Pinti M, Cevenini E, Nasi M, De Biasi S, Salvioli S, Monti D, et al. Circulating mitochondrial DNA increases with age and is a familiar trait: implications for ‘inflamm-aging’. Eur J Immunol 2014; 44:1552–1562.
191. Nelson JA, Krishnamurthy J, Menezes P, Liu Y, Hudgens MG, Sharpless NE, Eron JJ Jr. Expression of p16(INK4a) as a biomarker of T-cell aging in HIV-infected patients prior to and during antiretroviral therapy. Aging Cell 2012; 11:916–918.
192. Koen N, Du Preez I, Loots du T. Metabolomics and personalized medicine. Adv Protein Chem Struct Biol 2016; 102:53–78.
193. Gilbert JA, Quinn RA, Debelius J, Xu ZZ, Morton J, Garg N, et al. Microbiome-wide association studies link dynamic microbial consortia to disease. Nature 2016; 535:94–103.
194. Cassol E, Misra V, Holman A, Kamat A, Morgello S, Gabuzda D. Plasma metabolomics identifies lipid abnormalities linked to markers of inflammation, microbial translocation, and hepatic function in HIV patients receiving protease inhibitors. BMC Infect Dis 2013; 13:203.
195. Cassol E, Misra V, Dutta A, Morgello S, Gabuzda D. Cerebrospinal fluid metabolomics reveals altered waste clearance and accelerated aging in HIV patients with neurocognitive impairment. AIDS 2014; 28:1579–1591.
196. Ghannoum MA, Mukherjee PK, Jurevic RJ, Retuerto M, Brown RE, Sikaroodi M, et al. Metabolomics reveals differential levels of oral metabolites in HIV-infected patients: toward novel diagnostic targets. OMICS 2013; 17:5–15.
197. Srinivasa S, Fitch KV, Lo J, Kadar H, Knight R, Wong K, et al. Plaque burden in HIV-infected patients is associated with serum intestinal microbiota-generated trimethylamine. AIDS 2015; 29:443–452.
198. Serrano-Villar S, Rojo D, Martinez-Martinez M, Deusch S, Vazquez-Castellanos JF, Sainz T, et al. HIV infection results in metabolic alterations in the gut microbiota different from those induced by other diseases. Sci Rep 2016; 6:26192.
199. Routy JP, Mehraj V, Vyboh K, Cao W, Kema I, Jenabian MA. Clinical relevance of kynurenine pathway in HIV/AIDS: an immune checkpoint at the crossroads of metabolism and inflammation. AIDS Rev 2015; 17:96–106.
200. Effros RB, Allsopp R, Chiu CP, Hausner MA, Hirji K, Wang L, et al. Shortened telomeres in the expanded CD28-CD8+ cell subset in HIV disease implicate replicative senescence in HIV pathogenesis. AIDS 1996; 10:F17–F22.
201. Cao W, Jamieson BD, Hultin LE, Hultin PM, Effros RB, Detels R. Premature aging of T cells is associated with faster HIV-1 disease progression. J Acquir Immune Defic Syndr 2009; 50:137–147.
202. Valdez H, Connick E, Smith KY, Lederman MM, Bosch RJ, Kim RS, et al. AIDS Clinical Trials Group Protocol 375 Team. Limited immune restoration after 3 years’ suppression of HIV-1 replication in patients with moderately advanced disease. AIDS 2002; 16:1859–1866.
203. Tassiopoulos K, Landay A, Collier AC, Connick E, Deeks SG, Hunt P, et al. CD28-negative CD4+ and CD8+ T cells in antiretroviral therapy-naive HIV-infected adults enrolled in adult clinical trials group studies. J Infect Dis 2012; 205:1730–1738.
204. Kaplan RC, Sinclair E, Landay AL, Lurain N, Sharrett AR, Gange SJ, et al. T cell activation and senescence predict subclinical carotid artery disease in HIV-infected women. J Infect Dis 2011; 203:452–463.
205. Douek DC, McFarland RD, Keiser PH, Gage EA, Massey JM, Haynes BF, et al. Changes in thymic function with age and during the treatment of HIV infection. Nature 1998; 396:690–695.
206. van den Dool C, de Boer RJ. The effects of age, thymectomy, and HIV Infection on alpha and beta TCR excision circles in naive T cells. J Immunol 2006; 177:4391–4401.
207. De Francesco D, Oehlke S, Bürkle A, Wit FW, Franceschi C, et al. Biomarkers of ageing in HIV-positive individuals and matched controls. Conference on Retroviruses and Opportunistic Infections 2017; Abstract #672.

* Andrea Cossarizza and Jacqueline Capeau contributed equally to the writing of this article.


antiretroviral treatment; biomarkers; damage; HIV proteins; immune activation; inflammation

Copyright © 2017 Wolters Kluwer Health, Inc.