Folic acid supplementation improves microvascular function in older adults through nitric oxide-dependent mechanisms

Abstract

Older adults have reduced vascular endothelial function, evidenced by attenuated nitric oxide (NO)-dependent cutaneous vasodilatation. Folic acid and its metabolite, 5-methyltetrahydrofolate (5-MTHF), are reported to improve vessel function. We hypothesized that (i) local 5-MTHF administration and (ii) chronic folic acid supplementation would improve cutaneous microvascular function in ageing through NO-dependent mechanisms. There were two separate studies in which there were 11 young (Y: 22 ± 1 years) and 11 older (O: 71 ± 3 years) participants. In both studies, two intradermal microdialysis fibres were placed in the forearm skin for local delivery of lactated Ringer's solution with or without 5 mM 5-MTHF. Red cell flux was measured by laser-Doppler flowmetry. Cutaneous vascular conductance [CVC=red cell flux/mean arterial pressure] was normalized as percentage maximum CVC (%CVCmax) (28 mM sodium nitroprusside, local temperature 43°C). In study 1 after CVC plateaued during local heating, 20 mM NG-nitro-L-arginine methyl ester (L-NAME) was perfused at each site to quantify NO-dependent vasodilatation. The local heating plateau (%CVCmax: O = 82 ± 3 vs Y = 96 ± 1, P = 0.002) and NO-dependent vasodilatation (%CVCmax: O = 26 ± 6% vs Y = 49 ± 5, P = 0.03) were attenuated in older participants. 5-MTHF augmented the overall (%CVCmax = 91 ± 2, P = 0.03) and NO-dependent (%CVCmax = 43 ± 9%, P = 0.04) vasodilatation in older but not young participants. In study 2 the participants ingested folic acid (5 mg/day) or placebo for 6 weeks in a randomized, double-blind, crossover design. A rise in oral temperature of 1°C was induced using a water-perfused suit, body temperature was held and 20 mM L-NAME was perfused at each site. Older participants had attenuated reflex (%CVCmax: O = 31 ± 8 vs Y = 44 ± 5, P = 0.001) and NO-dependent (%CVCmax: O = 9 ± 2 vs Y = 21 ± 2, P = 0.003) vasodilatation. Folic acid increased CVC (%CVCmax = 47 ± 5%, P = 0.001) and NO-dependent vasodilatation (20 ± 3%, P = 0.003) in the older but not the young participants. Both local perfusion of 5-MTHF and supplementation with folic acid increase vasodilatation in ageing individuals through NO-dependent mechanisms.

Folic acid supplementation does not attenuate thermoregulatory or cardiovascular strain of older adults exposed to extreme heat and humidity

“…The obtained results provide arguments both for and against this possibility. Consistent with the possibility that folic acid supplementation improves cutaneous vasodilatation during heat exposure in older adults (Stanhewicz et al, 2015), greater serum folate concentrations and greater absolute values of local forearm cutaneous blood flow and vascular conductance were observed. In contrast, no effect of folic acid supplementation was observed for whole-limb forearm blood flow or vascular conductance.…”

“…Since folic acid supplementation improves nitric oxide availability (Stanhewicz & Kenney, ), it is not unreasonable to suggest that greater cutaneous blood flow/vascular conductance during local skin heating reflects improved nitric oxide availability. In support of this argument, local intradermal infusion of folic acid's active metabolite (5‐methyltetrahydrofolate) augments the nitric oxide contribution to cutaneous vasodilatation induced by local heating in healthy older adults (Stanhewicz et al., ).…”

“…Such interventions might be particularly effective in older adults who exhibit compromised cutaneous vasodilatation during heat exposure, largely due to age‐related reductions in nitric oxide availability (Holowatz & Kenney, ; Kenney, ). In fact, interventions that improve nitric oxide availability restore cutaneous vasodilatation of older adults to levels seen in young adults (Stanhewicz, Alexander, & Kenney, , ; Stanhewicz, Bruning, Smith, Kenney, & Holowatz, ; Stanhewicz, Greaney, Alexander, & Kenney, ). One such intervention is folic acid supplementation.…”

“…One such intervention is folic acid supplementation. Recent work has demonstrated that 6 weeks of high dose (5 mg day −1 ) folic acid supplementation augments cutaneous vasodilatation in older adults, restoring it to levels observed in young adults during passive heat exposure (Stanhewicz et al., ; Stanhewicz, Alexander, & Kenney, ). Importantly, these studies were performed under encapsulated conditions (i.e.…”

Ageing augments nicotinic and adenosine triphosphate‐induced, but not muscarinic, cutaneous vasodilatation in women

“…We previously reported that 30 m m ATP‐induced cutaneous vasodilatation is partly dependent upon by nitric oxide synthase‐ but not cyclooxygenase‐mediated mechanisms (Fujii et al., ) as assessed in a combined group of young men and women. However, several studies have demonstrated that ageing reduces nitric oxide synthase‐dependent cutaneous vasodilatation in a combined group of older men and women (Fujii et al., ; Stanhewicz, Alexander, & Kenney, ; Stanhewicz, Bruning, Smith, Kenney, & Holowatz, ). Furthermore, our previous work showed that ATP‐induced cutaneous vasodilatation at 3 m m occurred independently of nitric oxide synthase and cyclooxygenase in a combined group of young men and women (Fujii et al., ).…”