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HIV & Aging Clinical Recommendations
Chronic infection burdens repair and immune functions that are already slowing as a result of aging. Particularly important is the age-related shift in glutathione status, leaving a more pro-oxidant state in cells (Rebrin 2008).
The slower protein assembly of aging plays out as impaired muscle, organ, and bone repair. It also yields “immune senescence”—an inability to activate naïve T cells and generate memory T cells, (a glutathione dependent process) (Furukawa 1987).
Immune cell activity is sensitive to nutrition deficits; HIV infection alters gut cell structure, impeding all nutrient absorption, even with the use of ART (Knox 2000). Vitamin D deficiency was present in 42%, and B6 deficiency present in 37% of participants pre ART with minimal change at 48 weeks into ART therapy in the multinational PEARLS trial (Shivakoti 2016). Co-medications can also play a role in nutrient deficiencies: the risk of hypomagnesemia for a PLWH on a proton pump inhibitor is 3.16 times higher than HIV-negative persons (Sutton 2019). (Magnesium is crucial to nitric oxide availability for the vascular relaxation in the endothelium.) A study in Mexico found the key lymphocyte-dependent nutrients zinc and selenium were deficient in 25% to 50% of PLWH. These nutrient deficiencies correlated positively with higher inflammatory cytokine levels (Osuna-Padilla 2020). Remedial supplementation can help; in a US based study with, median age 45 and with zinc levels ≤75 µg/dL, repletion with zinc gluconate at 45 or 90 mg per day reduced biomarkers of inflammation and monocyte activation (Dirajlil-Fargo 2019).
With dependable access to quality medical care, PLWH now have a near normal life expectancy. However, diseases of aging like heart disease, diabetes, cognitive decline, and osteoporosis are happening at higher rates and at younger ages.
Antiviral therapies impact metabolism. NNRTI and PI-based regimens can alter glucose clearance and fat cell function, plus trigger mitochondrial malfunction. Protease inhibitors have diminished fat cell development and impeded GLUT4 activity, raising blood sugar and triglyceride levels (Lagathu 2019).
Sax noted an increasing amount of weight gain with each new drug class of ART therapy. The now broadly used integrase inhibitors (INSTIs) are associated with more weight gain than protease inhibitors or non-nucleoside reverse transcriptase inhibitors (NNRTI), with dolutegravir and bictegravir tied to more weight gain than elvitegravir/cobicistat (Sax 2019). The mechanism triggering the gain is not yet known fully known.
Persistent immune activation still exists in managed HIV infection. After 96 weeks of ART, soluble CD14, hyaluronic acid levels, and c-reactive protein levels are still somewhat elevated (Sereti 2017). Higher cardiac risk comes from inflammation and duration of infection, as measured by Carotid intima-media maximal thickness (c-IMT) and declining anti-inflammatory capacity (Desvarieux 2013).
Triant and Grinspoon provide a comprehensive review of the elements that contribute to cardiac risk, but still conclude, “Despite our vastly expanding knowledge of statins in HIV, no study has answered the question of whether statins effectively reduce cardiovascular events in this population”.(Triant 2017). While inflammation and immune activation are the novel factors that drive higher risk in HIV, Grinspoon especially calls attention to soluble CD163, a monocyte/macrophage activation marker, linked to the development of noncalcified unstable plaque that greatly increases CAD risk (Fitch 2010). How much can statin therapy help reduce cardiac risk in people with HIV? The REPRIEVE (pitavastatin) trial will provide better data for this. http://www.reprievetrial.org. In the general population, the Jupiter trial enrolled people with high-sensitivity C-reactive protein levels of 2.0 mg per liter or higher, indicating some inflammation present in their system. With 8901 people in each arm, a composite end point happened in 251 on placebo, versus 142 on rosuvastatin. This is a 1.2% drop in incidence, and a number needed to treat (NNT) of 83 (McAuley 2017).
Focus on nutrition for the gut for heart health. The gut mucosal barrier is affected by both aging and HIV infection. Breakdown in tight junctions and leakage through areas of apoptosis leads to systemic antigen exposure and immune activation (Wang 2014), a phenomenon first identified back on 2006 (Benchley 2006). Newer reports show that microbiome diversity positively correlates with CD4 T-cell counts and inversely with markers of microbial translocation and monocyte activation. In multivariate linear regression, for every age and sex-adjusted increase in the number of bacterial species, the CD4 T-cell count increased (Nowak 2015). Drs. El-Far and Tremblay at University of Montreal call the altered microbial diversity in HIV infection of people on ART a key target for prevention of cardiovascular disease (El-Far 2018).
Food provides vitamins, minerals, phytonutrients, and prebiotic fibers to maintain gut ecosystem integrity. When people routinely consume more than 30 different plant foods per week, they have a more diverse microbiome (Knight 2018). Diversity provides more phytonutrients, which can have a dynamic impact. For example, extra virgin olive oil at 50 grams per day (approx. 2 Tbsp.) for 12 weeks in a sample of over-50 people on ART, total cholesterol numbers dropped 5 points, and there was a trend ( p=0.13) for 1.2 point drop in C-reactive protein, along with 12 mg drop in LDL-C and 21 mg drop in triglycerides. In those taking integrase inhibitors, Bifidobacterium and Actinobacterium were more abundant, while those using NNRTI had a greater abundance of Bacteroidales and Bulleidia. There were gender differences in what microbes became more abundant too (Olalla 2019). [An interesting side note, rural dwellers have more gut species diversity than do urban dwellers. Diverse yard vegetation is associated with a reduced abundance of Clostridium sensu stricto and an increased abundance of Faecalibacterium and Prevotellaceae An abundance of Bacteroides is positively and strongly associated with the built environment (Parajil, 2020).]
Not surprisingly, foods can strain the integrity of the gut wall system. High carb-high fat meals, versus prudent diet regimens are associated with endotoxemia (Pendyala 2012). There is added burden on the innate immune response, and the resulting NFkB cytokine response, coupled with TLR4 activity contributes to insulin resistance (Ghanim 2009).
Beyond dietary elements, there are a few supplement trials focused on improved gut health and function. A symbiotic supplement ( 5 g of short-chain galacto-oligosaccharides, 10 g of long-chain fructo-oligosaccharides, and 5 g of L-glutamine) given for 16 weeks to a treatment naïve cohort experienced a decrease in bacterial DNA in plasma, plus a rise in beneficial bacteria such as Bifidobacterium, and reduction in harmful Clostridium. The CD4+ T cell count increased: median +102 cells/μL. The authors point out that this has ramifications for resource poor populations with limited resources for ART (Gonzáles-Hernández 2012).
Eight weeks of twice-daily supplementation with Culturelle (Lactobacillus rhamnosus GG (LGG) 6 bil CFU taken twice daily) reduced intestinal inflammation as measured by PET/MRI scans, plus diminished Enterobacteriaceae and Erysipelotrichaceae. However, there was no change in soluble markers of microbial translocation. The trial was in a group of both treated and ART naive people (Arnbjerg 2018).
In a 48 week Italian trial with a vigorous probiotic blend (Streptococcus salivarius ssp. Termophilus, Bifidobacteria breve, B. infantis and B. longum, Lactobacillus acidophilus, Lactobacillus plantarum, Lactobacillus casei, Lactobacillus delbrueckii ssp. Bulgaricus, and Streptococcus faecium), patients showed a statistically significant reduction in the levels of immune activation on CD4 T-lymphocytes, for both markers CD38 and HLA-DR and their simultaneous expression, lipopolysaccharide binding protein (LBP) and hsCRP settling to values comparable to controls (d’Ettorre 2015).
Another useful supplement to know about is the amino acid L-glutamine. As primary fuel for enterocytes, and secondary fuel for colonocytes, L-glutamine has been a vital treatment for intestinal permeability in medically stressed patients, from stem cell rescues, to burn victims to surgical cases (Wilmore 1997). Depletion of glutamine results in villus atrophy, decreased expression of tight junction proteins and increased intestinal permeability (Achamrah 2017).
For nearly fifteen years, glutamine has had some significant behind the scenes roles in HIV care. Coupled with cysteine, vit C and E, and selenium, glutamine gained notoriety as a supplement that could reverse wasting and help people regain lean body mass (Shabert 1999). It became even more popular as a solution for nelfinavir and lopinavir/ritonavir related diarrhea (Heiser 2004). Recently a small study of twelve PLWH, on stable ART for over a year with CD counts <500 investigated the effects of receiveing 12.4 gms per day glutamine for 30 days. The benefits included higher T cell counts, decreased CRP, and macrophage inflammatory protein-1β decreasing (Kupek 2019).
A Prevention Strategy
The degree to which gut distress in PLWH is causing increased morbidity is becoming clearer. While no definitive solution has been outlined, connoisseurship using information from the few interventions mentioned here, and drawing on other patient care situations leads to a viable prevention strategy to use now. Promoting appropriate dietary fibers or a FOS prebiotic supplement, with a reputable probiotic like LGG/Culturelle or VSL3 and 5 grams or more L-glutamine per day is low risk and could offer tremendous possible benefit.
Nutrition is about providing materials for the formation, operation, and repair of cells. The Mediterranean Diet, or Cretan-Mediterranean Diet, is the food plan with the best data on both immune (anticancer) and cardiac benefits (de Lorgeril 2013). The D.A.S.H. Diet preserves cardiac health, and reduces the risk of developing metabolic syndrome (Akhlaghi 2019).
Plant-based vegetarian diets seem to reduce disease risks, but this is epidemiological data that does not incorporate HIV disease elements such as fibrosed intestinal mucosa, altered gut-associated lymphoid tissue (GALT) status, and the redox burden of chronic infection as operative factors in assessing outcomes.
In directing people toward a Cretan-Mediterranean diet, one must consider some key elements. The diet has more fish and seafood, and less meat than other diets. There are liberal amounts of fruit and vegetables, including many wild greens. Whole grains are eaten as cereals and sourdough bread, not as pasta. Legumes, rich in magnesium, are eaten almost daily. Fat sources are nuts, olives, and olive oil. Dairy is more cheese than milk, especially goat and sheep milk cheeses. Chemically, the diet contains more selenium and glutathione, plus a healthier balance of omega-3 to omega-6 fats. It is very high in fiber and rich in antioxidants like vitamins C and E, plus resveratrol from red grapes/wine, and the anti-inflammatory oleuropein from olive oil. One research article reported that people on the island of Crete seem to consume 245 kilograms of plant material per year, (compared to the 150 kg in Italy and France, and 90 in Finland) (Simopoulos 2011).
Assemble the Daily Diet in a Series of Five Steps.
Step 1. Determine desirable protein foods, and eat them three times a day—generally breakfast, lunch, and dinner. Research is showing that aging people need more protein, up to double the RDA (Gaffney-Stomberg 2009). Loss of muscle in aging, known as sarcopenia, is a much bigger problem than in the general population and needs to be appreciated (Iannuzzi-Sucich 2002).
The American Heart Association stresses two 4-ounce servings per week of oily fish. As approximately 50% of Americans consume no fish each week, a daily fish-oil pill supplement should be considered. An average fish-oil pill will usually have 180 mg of DHA, the amount needed to replicate the 50% reduction in risk of senile dementia reported in Framingham studies. Up to 6 grams a day of fish oils have lowered triglyceride levels by almost 40% in an HIV population (Woods 2009).
As a matter of practicality, whey protein powder is a convenient and inexpensive additive to a meal, often added to breakfast cereal or protein-fruit smoothies. Trials of whey protein use in HIV populations have shown that it can sometimes raise CD4 counts (Sattler 2008) and frequently reverses glutathione (antioxidant enzyme) deficiency (Micke 2002). Whey can also improve osteoblast activity in bones (Xu 2009). Consumed dairy products should be fat-free or low-fat.
Step 2. Urge the eating of vegetables at both lunch and dinner. Three cups a day would be just a minimum amount to eat for the sake of obtaining Cretan-diet levels of minerals and phytonutrients. HIV-infected people consuming a dietary pattern that included higher intake of vegetables, fruits, and low-fat dairy foods, have significantly higher CD4 counts (Hendricks 2008).
Step 3. Encourage eating fruit three times per day to improve glutathione and glutathione peroxidase levels (Gil 2005). Eating fruit, including the traditional “apple-a-day,” provides the water-soluble fiber pectin, supporting beneficial gut flora, which lowers cholesterol numbers, C-reactive protein levels (Miller 1996), and body percent fat (Davis 2006) .
Step 4. Nuts and seeds contain essential oils that form cell membranes. A target is eating one handful of nuts and one of seeds every day. A trial of a Mediterranean Diet, supplemented with mixed nuts, proved more useful in heart disease prevention than did a low-fat diet (Estruch 2013). The fatty acid gamma linolenic acid (GLA), prominent in seeds (and spinach), lowers LDL-cholesterol, raises HDL-cholesterol (Levy 2017). Low GLA levels seem to be a risk factor for development of type2 diabetes (Kroger 2012). Dry cracking skin at the edge of fingernails and on finger tips can be a symptom of low GLA levels. Consuming ¼ cup raw seeds daily, or taking 2 grams evening primrose oil covers GLA needs. People with a GLA deficiency gain fat in the abdomen, see cholesterol and triglyceride counts rise and HDL-cholesterol levels drop (Tremblay 2004) precisely the common body shape and blood lipid changes seen in lipodystrophy.
Step 5. Starches (carbohydrates) are the remaining part of fuel and food needs. Legumes, technically a protein-rich starch, are an important component of the Mediterranean diet, providing fiber, plant protein, and magnesium. Higher magnesium intake is inversely related to cardiac and cancer mortality (Guasch-Ferre 2014). In both the D.A.S.H. Diet and Mediterranean Diet, higher magnesium intake is correlated with preservation of cognitive function in aging (Wengreen 2013). Select starch portion sizes wisely in aging and on ART; oversized servings of starches tend to turn to fat faster (Wolever 2003). Avoid simple sugars, and eat whole grains.
In addition to assembling a diet that focuses on variety, nutrient density, and amounts, the calories from added sugars and saturated fats, along with sodium should be limited (USDA 2015).
Inflammation predicts disease and mortality in treated HIV infection (Marconi 2020). Common targets are osteoporosis, vascular disease risk, sarcopenia, loss of cognitive function, fatigue/frailty, and immune senescence.
Subtle nutrient deficiencies play a role in all of these problems. Using comprehensive nutrition therapy to treat degenerative processes offers the opportunity to avoid increased pharmacologic burden in a population where side effects are especially likely.
In the internet age, many consumers are familiar with nutritional supplements in HIV treatment. Below is a review of conditions and studies that could improve clinicians’ comfort level with the vitamin, mineral, and other supplement interventions their PLWH are utilizing. Nutrition therapy can help in situations where treatments are nonexistent or have low efficacy.
Cholesterol levels do not account for all cardiac and vascular disease risk. Carotid artery occlusion is associated with longer time on ART. Subtle B-vitamin deficiencies, seen as higher homocysteine levels, were a cause of carotid artery narrowing in the Framingham study (Selhub 1996). B-vitamin-dependent enzymatic deficiencies in the elderly cannot be detected in serum B-vitamin-level tests. This speaks to the utility of supplementing with B-complex vitamins in this population.
As stated before, the American Heart Association recommends eating fish twice a week in general, and consuming 1 gram a day of EPA/DHA for people with heart disease. Low HDL is common in this population. This can be reflective of essential fat deficiency, and of lower redox capacity. In HIV-uninfected people, N-acetylcysteine at 1200 mg to 3600 mg/day range can raise HDL cholesterol by 10 points (Franceschini 1993). Improving HDL level is an important marker for reducing risk from cardiac events even into a patient’s 80s.
As discussed previously, attention to gut wall integrity and dysbiosis is an emerging topic. Pay more attention to increasing dietary fiber, and investigate L-glutamine and probiotic supplementation.
Remember, sedentary behavior is a major (modifiable) cardiac risk factor. The amino acid L-Glutamine, along with EPA/DHA fatty acids, improves exercise capacity in patients with heart failure (Shahzad 2011).
Chronic inflammation along with some ART meds initiates systemic bone loss. Vitamin D and calcium supplements should be considered for general bone health, but are generally not enough to reverse thinning bones if confirmed osteoporosis without other treatmentOne study using an algae-derived calcium, with strontium, boron, magnesium, plus vitamins D and K2 supplements, showed increase in BMD in 6 to 12 months in older people (Michalek 2011).
Many older people come late to care, with very low CD4 counts. Adequate glutathione levels are necessary for generating T cells. Supplementing L-glutamine at 5 grams per day, is helpful for this. A B-complex 25 with vitamin C pill improves T-cell numbers in HIV disease (Fawzi 1998). Use of protease inhibitor therapy puts people at risk for low vitamin B12 levels (Woods 2003) as does taking proton pump inhibitors (Marcuard 1994). A multivitamin improves T-cell and NK-cell counts and reduces sick days in the elderly (Barringer 2003). Vitamin E at 200 units improves immune responses to vaccines. (Meydani 1997). Co-enzyme Q10 reverses lymphadenopathy and improves immune function (Folkers 1988). It also protects endothelium in people on statins with diabetes (Hamilton 2009).
From a nutrition perspective, frailty is simply failure to achieve adequate repair of many cell and organ systems. L-glutamine plus antioxidant vitamin supplementation reverses HIV wasting. Glutamine alone raises both glutathione and mood levels (Young 1993). L-carnitine supplements reverse neuropathy symptoms (Youle 2007) and lipodystrophy problems (Benedini 2009). At 2 grams per day it has improved muscle action in heart failure trials (Rizos 2000). Coenzyme Q10 can increase ejection fractions in seniors, improving constitutional energy levels (Langsjoen 1994).
The commercial vitamin industry now has a number of products aimed at the senior market. These tend to include a higher strength B-complex component, plus higher amounts of vitamins C and E, zinc and selenium, and magnesium component.
US Dietary Guidelines. 2015.