Accelerated Aging process in Patients Living with HIV: Role of Mitochondrial Dysfunction.

Introduction

Owing to the introduction of successful antiretroviral therapy (ART) HIV became a chronic disease. Despite effective virologic control in plasma and a decrease in the overall mortality, people living with HIV (PLWH) have a high prevalence of non-AIDS defining illnesses (cardiovascular, respiratory, neurologic, metabolic, renal, and liver disease) along with different types of malignancies.^1–12 Recently it has been increasingly reported that well controlled PLWH on ART have increased metabolic complications like weight gain, insulin resistance, fatty liver, and metabolic syndrome^13–16 all of which can affect lifespan and healthspan. Since most of those chronic diseases are also seen during normal aging with progressing low-level chronic inflammation a new concept named “Inflammaging” has been adopted, on which well-controlled PLWH on ART experience a faster progression to aging-related organ dysfunction compared to HIV(-) controls of the same chronological age.^2,4,5,9 To support the above hypothesis studies have shown an increase^17–21 of age-associated DNA methylation in PLWH that is consisting with an accelerated aging²² which is partially restored with ART. One of the main reasons of accelerated aging on PLWH seems to be related to chronic low-grade inflammation and persistent immune activation but the ultimate culprit remains largely unknown and has been debated extensively in the literature.

Aging in the general population has been linked to progressive mitochondrial dysfunction (MD), which has become as one of the “Hallmarks of Aging”^23,24 along with chronic inflammation, altered intercellular communication, stem cell exhaustion, cellular senescence, dysregulated nutrient sensing, disabled macroautophagy, loss of proteostasis, epigenetic alterations, telomere attrition, genomic instability, and dysbiosis^25,26 (see Figure 5). We hypothesize that HIV-associated-mitochondrial dysfunction (HIVAMD) may be the main culprit of the accelerated aging process and most of the age-associated chronic diseases documented at early ages compared with HIV negative controls. The objective of this review is to propose a mechanism that can explain the origin of HIVAMD and accelerated aging on PLWH on ART with emphasis on the cross-talk between certain metabolic and immunological pathways (like activation of CD38 and IDO-1 activity) in order to define clear therapeutic targets for future pragmatic prospective randomized clinical trials

MECHANISMS OF HIVAMD

1. MECHANISMS OF HIVAMD

The most important mitochondrial function is the generation of energy in the form of ATP (Oxidative Phosphorylation or OXPHOS) from nutrients (glucose, fatty acids) through the electron transfer between specific protein complexes (complex proteins 1,2, 3, 4). Those protein complexes are located in the Inner Mitochondrial Membrane (IMM). This protein complex which is fed by electrons generates a proton gradient between the matrix and the Intermembrane Space ("chemical gradient" or "mitochondrial membrane potential") used by the ATP synthase to generate ATP. "Disruption" of the flow of electrons throughout the protein complex or “leaks” of H+ has profound consequences for mitochondrial bioenergetics and cell homeostasis²⁷.

“……In the presence of oxygen a healthy mitochondrial function can be described as an uninterrupted flow of electrons through the electronic transfer chain (etc) (without electron leaks and with adequate amounts of nadh and fadh) with generation of a chemical gradient of protons used by the atp synthase to generate atp with minimal production of ros in the context of an adequate amount of anti-oxidants. Also, there has to be a balance between nutrients supply and energy demands in order to avoid mitochondrial stress and overload…” (figure 1)

Figure 1.Healthy Mitochondrial Function.

IMM = Inner Mitochondrial membrane. ROS = reactive oxygen Species. MC = Mitochondrial Complex. (+++) matched energy supply to energy demands.

During hemostatic conditions the mitochondrial energy production is the result of a perfect coordination between energy supply (NADH – FADH or “Electrons donors” from Glycolysis and the Krebs or TCA Cycle) and energy demands (ATP demand by the ATP synthase). During normal functioning there is “no leak” of electrons (or "system overload") within the protein complexes and there is generation of an adequate membrane potential of H+ enough to promote the conversion of ATP from ADP (Figure 1).

In a recent review²⁸ and, as an interesting analogy, if we compare the flow of electrons through the IMM with "water flow in a hose", the electrons donors (NADH for example) or energy supply will control the hose inlet meanwhile the ATP demands (energy demands) will control the hose outlet (Figure 2). In the case of excess of supply without the equivalent ATP demand there will be an increase on the pressure of the system with “leaks of water” through the cracks of the hose (electrons leaks) with generation of ROS excess (Oxidative Stress).

Figure 2.Comparison Between the Mitochondrial Respiratory Chain and a Hose.

IMM = Inner Mitochondrial membrane.

MD due to overnutrition during obesity (increased of the supply of nutrients without concomitant increase of the energy demands) can cause system overload and electrons to “leak” which can affect the chemical proton gradient, and cause an excess of Reactive Oxygen Species (ROS). ROS excess can cause mitochondrial damage mainly through mutations of the circular mitochondrial DNA (mDNA) causing accumulation of damaged mitochondria.²⁷ When there is “uncoupled” oxygen consumption to ATP production there is dysregulated metabolism and mitochondrial stress. Figure 3 shows how overnutrition cause electrons to “leak” with system overload decreasing the proton gradient, hence, affecting the production of ATP by the ATP synthase with increased ROS generation (decreasing Bioenergetic efficiency). On the context of overnutrition, protons can cross through the internal mitochondrial membrane (not trough the ATP synthase) to generate ATP using the chemical gradient but using “uncoupled channels” which decrease the proton gradient and energetic efficiency with generation of heat²⁸ [compare Figure 1 with Figure 3].

Figure 3.Mitochondrial Function in the Context of Overnutrition-Obesity.

IMM = Inner Mitochondrial membrane. ROS = reactive oxygen Species. MC = Mitochondrial Complex. Seen “uncoupled” energy supply (+++++)/demands (+) ratio.

In the case of overnutrition the mitochondria will synthetize uncoupling proteins (UCPs) which will “create pores” within the inner mitochondrial membrane (usually not permeable in normal conditions) to allow protons to go back to the matrix and somehow “decompress” the overloaded system with less production of ATP and energy dissipation in the form of heat.^29,30 This mechanism may provide some protection or compensation against oxidative stress as a result of excessive nutrient intake without the corresponding energy (ATP) demands (Figure 4).

Figure 4.Uncoupling proteins (UCPs) allows protons to move from the IMM to the Matrix decreasing the membrane potential and the proton gradient, hence, decreasing the production of ATP (uncoupling) by the ATP synthase.

IMM = Inner Mitochondrial membrane. ROS = reactive oxygen Species. MC = Mitochondrial Complex

2. Mitochondrial Dysfunction (MD), Age-Associated Cellular Decline (AACD), and Aging in PLWH

It is clear now after years of research that mitochondria is not only the “Powerhouse of the cell” but a critical organelle with many other important cellular functions.

“….Mitochondria, which originally was a Prokaryote cell (bacteria), was incorporated into Eukaryote cells millions of years ago through endosymbiosis with the main goal of generating energy for cell growth and differentiation in a symbiotic relationship. As a prokaryote cell, they conserved the double lipid membranes and circular DNA with capacity to divide (Fission) and the capacity of mixing genetic material between them (Fusion) to overcome the potential harmful DNA mutations……but they cannot survive alone and are semi-autonomous…”^17–21

Mitochondria acquired many regulatory functions through millions of years of evolution including cell signaling, regulation of gene expression in nuclear and mitochondrial DNA, cell growth and apoptosis (both intrinsic or extrinsic), calcium regulation, iron compartmentation, and modulation of autophagy.³¹

MD in general has been associated with many diseases like optic neuropathy, retinopathy, deafness, liver failure, anemia, diabetes, peripheral neuropathy, renal failure, cardiomyopathy, muscle weakness, exercise intolerance, cancer, and neurodegenerative diseases, between others .³² MD has also became recognized as one of the main pillars of Age-Associated Cellular Decline (AACD)²⁶ (Figure 6) on which frailty, sarcopenia, chronic fatigue, and metabolic syndrome are typical clinical features. Other drivers of AACD highly related with MD are the decline of NAD+ with aging^33,34 (with decrease in ATP production) and the decline in glutathione (protective against Reactive Oxygen Species -ROS-) along with lifestyle and environmental-social factors including the overconsumption of Ultra processed foods (UPFs) (see Figure 6). It is extremely important the decline of NAD+ with age which may have a profound metabolic impact favoring accelerated aging and decline in energy production (see below sections). Of note, NAD+ declines up to 50% between 40 and 60 years of age.^33,35–38

Figure 5.The Hallmarks of Aging including on PLWH

PLWH have many of the hallmarks of aging but we will be focused mainly on MD, senescence, and chronic inflammation.

Figure 6.AACD and Mitochondrial Dysfunction are highly related and have common causes and clinical translation.

UPFs= Ultra processed foods

HIVAMD may be the culprit, at least in part, of the age-related comorbidities seen in PLWH on ART like neurodegenerative, cardiovascular, and metabolic diseases. All of the hallmarks of aging are observed on PLWH but at early ages.²⁷ In particular, HIV-induced-senescence is of particular concern since it predisposes to chronic inflammation, immunological failure, immune activation, HIVAMD, and further senescence of bystander cells (senescence-induced-senescence).³⁹ It is well known that HIVAMD is associated with a decrease on muscle function, cardiorespiratory fitness, and cognitive function.⁴⁰

“…..Of note Senescence, Chronic inflammation, Immune activation and Mitochondrial dysfunction are all closely related and interconnected^24,27,41 and can potentially explain the accelerated aging observed on PLWH on ART…”

For clinicians highly trained in patient care all the above concepts may sound abstract without a clear clinical translation at the bedside but it’s important to recognize that those pathophysiologic features are highly related and interconnected and that their direct consequences are clinically recognized syndromes seen during rounds (see Figure 7).

Figure 7.Pathophysiology of Aging on PLWH. All the concepts are interconnected but with the same clinical consequences

SASP = senescence-associated secretory phenotype; ROS = reactive oxygen species.

"……HIV WAS NOT PROGRAMMED THROUGH EVOLUTION TO INTERACT WITH BACTERIAL DNA, HENCE, HIV PRO-VIRAL DNA IS NOT INTEGRATED INTO THE MITOCHONDRIAL DNA (MDNA). HOWEVER HIV, ITS CONSEQUENCES, OR IT’S TREATMENT STILL CAN HAVE PROFOUND HARMFUL CONSEQUENCES FOR MITOCHONDRIAL FUNCTION CAUSING HIVAMD….."45

3. There are several mechanisms for which HIV, it’s consequences or it’s treatment can cause HIVAMD, some of them are

A)HIV causing Chronic Inflammation and Immune-activation promoting Oxidative Stress (see section below specifically about systemic inflammation).

B)HIV and mDNA Repair proteins

It is well known that mDNA is in charge of the synthesis of many proteins that are essential for the correct functioning of the electron transport chain (ETC)²⁷ in addition to nuclear DNA codified proteins. As explained above any insult able to cause MD will cause an excess of ROS which itself can damage mDNA and produce mDNA mutations. The accumulation of mutated mDNA without repair or mitophagy can lead to MD with further increase ROS in a persistent vicious cycle. It has been shown that the HIV itself can affect the production of some proteins in charge of mDNA repair like ATM, ATR, DNA-PKs, TOP I/II alpha, and p53.²⁷

B)HIV and immune-senescense

Senescence can be defined a state of irreversible proliferative arrest⁴⁰ triggered by many factors: excessive replication, oncogene activation, telomere shortening, DNA damage, hyperglycemia, increased ROS, chronic infections, and protein accumulation. Senescent cells secrete a significant amount of proteins, cytokines, lipids, growth factors, and metabolites called senescence-associated secretory phenotype (SASP)⁴². Senescent cells can actually drive aging and aging-related diseases⁴⁰ and it is highly linked to MD. It has been described that SASP is able to produce mitochondrial dysfunction in bystander neighboring cells through senescence-induced-senescence³⁹ which may also be present during HIV infection in certain tissues. As one of the hallmarks of Aging mentioned above, immune-senescence is another characteristic of chronic HIV infection, even when properly treated with ART .⁴⁰ As an example, the monocyte phenotype of young viremic HIV+ males looks similar to aged HIV (-) controls (increased CD11b, CD14+CD16+ and downregulation of CD62L and CD115)(13). PLWH show an increased proportion of terminally differentiated cells in the CD4 and CD8 pool with markers of senescence like CD57+ (12). Other markers of senescence during HIV infection are the decrease in the number of naïve T cells, increase of TNF-alpha, sCD163, and sCD14 (13). A loss of mitochondrial efficacy and bioenergetics with increase of ROS is found in senescent tissues.

Some of the mechanisms from which senescence may cause HIVAMD are²⁴:

• Production of mDNA mutations through increased ROS

• SASP can promote systemic inflammation through the secretion of pro-inflammatory cytokines affecting directly mitochondrial function as a result of ROS accumulation.

• Promotion of an Abnormal ratio between mitochondrial fusion/fission (altered mitochondrial biogenesis or dynamics)

• Decreased mitophagy (autophagy) of damaged mitochondria with accumulation of ROS

• Alteration of electron transfer chain components, hence, ATP production.

• Promotion of mitochondrial metabolic changes with shifts of nutrient utilization consequently with impaired ATP production.

• Persistent activation of mTOR pathways: Increased mTORC1 is associated with decreased mitophagy with accumulation of defective mitochondria. During senescence mTOR is persistently activated.

• Decrease function of SIRT3, SIRT4, and SIRT5 (mitochondrial Sirtuins): Depletion of SIRT3 induces senescence.

• Abnormal NAD+/NADH ratio (controlled by CD38+ activation)

• Increased Ca+2 influx with mitochondrial overload

“….OXPHOS can be highly affected during senescence with decrease activity on some of the electron protein chain components favoring glycolytic pathways in the cytosol, hence, pro-inflammatory pathways with less energy production (ATP)…²⁴”

“….under normal conditions damaged mitochondria activate apoptotic programs within the cell with cell death through the NLRP3-ASC-Pro caspase-1 pathway and “pyroptosis”⁴³ but senescent cells may go on for long periods of time promoting more senescence, HIVAMD, and inflammation in a vicious cycle…⁴¹”

D) HIV Proteins and HIVAMD

Most of the encoded viral HIV proteins like structural proteins (Gag, Pol, Env), regulatory elements (Tat, Rev), and accessory regulatory proteins (nef, Vpr, Vif, and Vpu) may cause HIVAMD.²⁷

• The Env gene codifies for gp120 which has been shown to promote apoptosis through mitochondrial pathways affecting the ETC functioning, ATP synthesis, and finally releasing Cytochrome c with activation of caspases 9 and 3⁴⁸.

• Vpr is also capable of induce apoptosis through the intrinsic apoptotic pathways (cytochrome c) as the gp120 does.^44,45 Vpr can also damage or decrease the number of copies of the mitochondrial fusion protein mitofusin 2 (Mfn2) which is essential for functioning, fusion, and cellular trafficking with other organelles like the endoplasmic reticulum (ER) interfering with their mutual cellular coordination and communication.²⁷

• Tat has been shown to trigger apoptosis (intrinsic pathway) through downregulation of bcl-2 (an anti-apoptotic protein) with can also affects neighboring cells.²⁷ Tat also was shown to inhibit the telomerase activity inhibiting the addition of telomeric sequences to DNA which usually evades cell senescence.⁴⁶

• The HIV protein Nef activates T cells which creates new targets for infection through CCR5 or CXCR4 receptor in addition to promote apoptosis of bystander cells.²⁷ Nef also has been shown to inhibit autophagy and mitophagy with accumulation of cellular waist and damaged mitochondria⁴⁷ affecting cellular energy production.

“….Some evidence shows that chronically latently infected HIV cells shows downregulation of genes responsible for mitochondrial biogenesis²⁷ along with increased oxidative stress and shorter telomeres all which can affect mitochondrial function. May HIVAMD be related to viral persistence? May HIV “hijack” the mitochondria machinery in order to persist?….”

E) ART and HIVAMD

A the beginning of the ART era Zidovudine or Stavudine were able to greatly affect mDNA with significant known adverse effects (lactic acidosis, lipodystrophy, insulin resistance, cervical fat-pads, hyperlipidemia and fat wasting (face and limbs) causing a particular physical phenotype easily recognized by trained clinicians. With recent advances on ART newer drugs have now a much better safety profile and years of experience on its use and safety. However it is known that Nucleoside-analog reverse transcriptase inhibitors (NRTIs) still are able to inhibit DNA polymerase gamma (responsible for replication of mDNA),⁴⁸ hence, affecting oxidative phosphorylation and mitochondrial biogenesis. Other classes of ART like non-nucleoside analog reverse transcriptase inhibitors (NNRTIs), Integrase inhibitors (INSTIs), and Protease inhibitors (PI) can also affect mitochondrial function without inhibiting the polymerase gamma which has been documented in a recent study.^27,48

Summary of the effects of ART on mitochondrial function:

1. NRTIS:

   1. Inhibition of Polymerase gamma

   2. Reduction of mDNA copies

   3. Reduction of mDNA proteins

   4. Inhibition of ETC proteins

   5. Decrease cellular ATP reduction (inhibition of ADP/ATP translocation through channels)

   6. Increase oxidative stress

   7. Decrease in the membrane potential difference (less H+ gradient)

2. NNRTIS:

   1. Increased apoptosis (Cytochrome c release)

   2. Increased oxidative stress

   3. Decrease in the membrane potential difference.⁴⁹

3. PIS:

   1. Increased oxidative stress

   2. Decrease in the membrane potential difference

   3. Decreased OXPHOS capacity

   4. Increased ER stress

   5. Increased apoptosis²⁷

   6. Reduced mDNA copies

4. INSTIS:

   1. Metabolic switch from OXPHOS to Glycolysis

   2. Increased mDNA copies

   3. Increased oxidative stress

   4. Respiratory chain deficiency

F) HIV and Overstimulation of CD38

Overactivation of CD38(+), as seen on PLWH, can cause HIVAMD through multiple mechanisms (Figure 8):

• Decreased Cytosolic NAD+ with impairment of ATP production

• Decreased Cytosolic Mitochondrial NAD+ with less activation of Sirtuins1-6 (NAD+ is their main co-factor) which are protective against MD, ROS, and DNA mutations and at the same time activate PGC-1 alpha.

• CD38 activation can cause an increase of pro-inflammatory cytokines with subsequent systemic inflammation / immune-activation and secondary mitochondrial damage due to oxidative stress (ROS accumulation) with structural mitochondrial damage (mDNA, lipids, and other mitochondrial structures). Of note, persistent immune-activation can produce “immune exhaustion”.

• Increased glycolytic / pro-inflammatory pathways (“metabolic switch” or “Warburg effect”) through the recruitment of Glut-1 receptors to the cell surface which can cause increase oxidative stress (ROS) with mDNA damage and accumulation of damaged mitochondria. Exhausted immune cells can switch from OXPHOS to Glycolysis (metabolic reprogramming) which can be detrimental for mitochondrial function.⁵⁰

• Secondary catalytic products of NAD+ through CD38(+)(ADPR, cADPR, NAADP) can open calcium channels and decrease mitochondrial integrity with apoptosis.

• Immune exhaustion through the PD-1/PD-L1 signaling pathway can potentially also impair mitochondrial function

“…of note, inhibition of CD38 dramatically increases the levels of NAD+ in normal and obese mice⁵¹…”

Figure 8.Relationship between CD38 activation, NAD+ depletion, and Mitochondrial dysfunction (HIVAMD), the possible cause of accelerated aging.

HIVAMD = HIV Associated-Mitochondrial Dysfunctio; AACD = Age-Associated Cellular Decline.

G) Overactivation of Indoleamine 2,3 dioxygenase 1 (IDO-1) and NAD+ depletion during HIV infection may promote HIVAMD

The Kynurenine pathway has been highly conserved on different species from yeasts to humans.⁵¹ IDO-1 plays a central role in HIV pathogenesis through its immunoregulatory effects which can be reviewed elsewhere.^52–60 (for more details about IDO-1 see our recent review: https://doi.org/10.59541/001c.84063). LPS, HIV-1 Tat protein,⁶¹ IFN-alpha/gamma, Aryl Hydrocarbon Receptor (AHR) activation, Toll-like receptors stimulation, TNF-alpha, NAD+ depletion, and loss of Th17 cells all can induce and activate this enzyme. IDO-1 can be increased in many immune cells like macrophages, glial cells, antigen-presenting cells, lymphocytes, and natural killer cells (NKc).⁵¹ A study showed that there is a correlation between IDO-1 activity and HIV DNA in blood, Immune-activation, and T cell exhaustion.⁵⁴ IDO-1 catalyzes the conversion of Tryptophan to N-formyl-D-kynurenine and it’s metabolites and increases the Kynurenine/Tryptophan ratio. Also IDO-1 promotes the conversion of naive T cells to Tregs,⁵⁴ hence, it can modulate the immune response. In the kynurenine metabolic pathway starting from Tryptophan (TRP) one of the last steps is the generation of NAD+ from Quinolinic acid due to the enzyme Quinolinate phosphoribosyl transferase (de-novo NAD+ synthesis pathway). Any disbalance on the amount of available tryptophan or its intermediate metabolites could negatively impact the generation of NAD+ from quinolonic acid (see Figure 9).

Figure 9.Kynurenine pathway as a possible mechanism of accelerated aging/HIVAMD on PLWH. This pathway can either drive de-novo NAD+ generation or intermediate metabolites that can potentially cause mitochondrial dysfunction.

HIVAMD = HIV Associated-Mitochondrial Dysfunction

Two hypothesis could link CD38 activation –> NAD+ depletion –> IDO-1 activation –> HIVAMD –> Aging:

“….Hypothesis #1 = Overactivation of CD38 on PLWH produce a depletion of NAD+, which, in turn, accelerate the IDO-1 metabolic pathway in order to generate de-novo NAD+. The increased flow of reactions through the Kynurenine pathway could overproduce 3HK, 3-HAA, or QA causing HIVAMD….” (Figure 10)

“….Hypothesis #2 = Overactivation of CD38 during HIV infection generates immune activation with increased secretion of pro-inflammatory cytokines (especially TNF-alpha) with subsequent activation of IDO-1 not mediated by NAD+ overconsumption….”. (Figure 10)

Figure 10.Hypothesis on how overactivation of CD38 in PLWH can cause NAD+ depletion, IDO-1 activation, HIVAMD, and accelerated aging. CD38 can cause direct activation of IDO-1 due to NAD+ depletion or indirectly through immune activation and generation of pro-inflammatory cytokines. Black arrows shows direct/indirect mechanisms.

HIVAMD = HIV Associated-Mitochondrial Dysfunction; 3HK = 3-hydroxykynurenine; 3-HAA = 3-hydroxyanthranilic acid; QA = Quinolinic Acid; AACD = Age-Associated Cellular Decline

It could be also significant the cross-talk between CD38, IDO-1, and Tregs especially related to the increased Tregs/Th17 seen during HIV-induced dysbiosis. In the following graphics we can see the cross-talk between CD38, IDO-1, and Tregs (Figure 11):

Figure 11.

H) How HIV-associated Systemic inflammation (Inflammaging) can cause HIVAMD?

Even though the relationship between systemic inflammation on PLWH and HIVAMD is bidirectional (it’s not clear which phenomena happens first) there is a clear relationship between systemic inflammation and mitochondrial dysfunction even though the exact mechanisms have not been explored in detail. It is known that even well-controlled HIV on ART still have significant increase of inflammation and immune-activation compared to HIV uninfected controls, thought to be independent of viral replication. C-reactive protein, TNF-alpha, IL-6, IFN-gamma and D-dimer remain elevated even after effective control of viral replication with ART.⁵⁷ An increase of CD14, a surrogate of microbial translocation and monocyte activation predicted mortality on PLWH in one study.⁵⁷ Chemokines like IL-8, RANTES, CCL2, and Interferon gamma-induced protein 10 (IP10) remain elevated even during effective ART.⁶² CXCL13 (a marker of immune activation) is elevated in PLWH compared to HIV uninfected controls and is correlated with HIV VL, CD4 T cell count, CD4/CD8 ratio, LPS, sCD14, (1→3)-β-D-Glucan, total IgG, TNF-α, Kynurenine/Tryptophan ratio, and frequency of CD38+HLA-DR+ CD4 and CD8 T cells.⁶³

“….ART improves the systemic inflammatory environment but does not eliminate the persistent low-level chronic inflammation…”

The sources of inflammation on HIV patients on ART exceed the objective of this review and can be found elsewhere. Some hypothesis on how HIV-induced systemic inflammation can cause HIVAMD are the following:

• Chronic systemic inflammation and Immune activation can stimulate the production of reactive oxidative species (ROS) and reactive nitrogen species (RNS) causing oxidative stress which can be detrimental for some mitochondrial structures like mDNA, proteins or mitochondrial lipids⁶⁴ impairing mitochondrial function and starting mitochondrial stress signals.

• Chronic inflammation can impair mitophagy (the autophagy of damaged and defective mitochondria) which can led to the accumulation of damaged/defective mitochondria with decreased energy production and increased oxidative stress.⁶⁵

• Some specific cytokines like TNF-alpha, IL-6, and Interleukin-1-beta can impair the mitochondrial membrane potential and interfere with the OXPHOS process directly.⁶⁶

• Some evidence also suggest that the nuclear factor kappa B (NF-kB) signaling pathway activated during systemic inflammatory signals is detrimental for mitochondrial function.⁶⁷

• Systemic inflammation may also affect mitochondrial biogenesis (formation of new mitochondria) in response to increased metabolic needs.

• The persistent activation of immune cells during chronic HIV can cause “immune exhaustion” highly linked to mitochondrial dysfunction since immune cells have extremely high energy demands.⁶⁸

Of note HIVAMD can also potentially cause or exacerbate systemic inflammation.

Figure 12.

Conclusions and Future Perspectives. A Pragmatic Approach to Reach a Functional Cure with a Geroscience-guided Approach

PLWH are suffering from a significant number of age-associated diseases at an accelerated rate, diseases that are usually seen in older populations, hence, we could theorize that the approach used on GEROSCIENCE for certain clinical trials could also be applied to this population.

HIVAMD may play a central role on the pathogenesis of the accelerated aging process and represent one of the most important hallmarks of aging of PLWH which could be a target for pharmacological and non-pharmacological interventions in prospective randomized clinical trials. New immune-metabolic and nutritional pathways will need to be explored in order to prevent, and, may be revert, inflammaging on PLWH. It is now clear that ART only partially reverses some of the metabolic and immunological abnormalities on PLWH only controlling the gross HIV replication in plasma and protecting against the progression to AIDS. Here we describe an hypothesis about the possible link between HIVAMD, CD38, IDO-1, NAD+ depletion, chronic inflammation, and immune-activation with the accelerated aging phenomena. We emphasized the central role of NAD+ depletion on HIVAM along with a deficit on OXPHOS pathways.

To the best of our knowledge this is the first comprehensive description of the possible relationship between HIVAMD, Aging, inflammation, immunesenescense, AACD, CD38, and IDO-1 activity with the goal to define possible therapeutic targets for future prospective clinical trials. Future prospective randomized trials are highly needed in order to test the above hypothesis and try to reverse- or improve HIVAMD. A pragmatic approach with dietary and pharmacological interventions in proof-of-concept preliminary studies may need to be explored first within the community, on community hospitals, and/or non-profit organizations. Pragmatic, simple, small and proof-of-concept studies may give raise to large prospective randomized studies on large academic centers.

Some of the pragmatic studies to counteract HIVAMD based on current geriatric clinical trials could explore the following concepts (Table 1-2):

Table 1.Concepts to explore on Clinical Trials

Table 2.Concepts to explore on Clinical Trials Continuation