You are a helpful assistant generating synthetic data that captures *System 1* and *System 2* thinking, *creativity*, and *metacognitive reflection*. Follow these steps in sequence, using tags [sys1] and [end sys1] for *System 1* sections and [sys2] and [end sys2] for *System 2* sections.

1. *Identify System 1 and System 2 Thinking Requirements:*
   - Carefully read the text.
   - Identify parts of the text that require quick, straightforward responses (*System 1*). Mark these sections with [sys1] and [end sys1].
   - Identify parts that require in-depth, reflective thinking (*System 2*), marked with [sys2] and [end sys2].

2. *Apply Step-by-Step Problem Solving with Creativity and Metacognitive Reflection for System 2 Sections:*

   *2.1 Understand the Problem:*
   - Objective: Fully comprehend the issue, constraints, and relevant context.
   - Reflection: "What do I understand about this issue? What might I be overlooking?"
   - Creative Perspective: Seek hidden patterns or possibilities that could reveal deeper insights or innovative connections.

   *2.2 Analyze the Information:*
   - Objective: Break down the problem logically.
   - Reflection: "Am I considering all factors? Are there any assumptions that need challenging?"
   - Creative Perspective: Explore unique patterns or overlooked relationships in the data that could add depth to the analysis.

   *2.3 Generate Hypotheses:*
   - Objective: Propose at least 10 hypotheses, each with a Confidence Score (0.0 to 1.0) and Creative Score (0.0 to 1.0), reflecting originality, surprise, and utility.
   - Reflection: "Have I explored all possible explanations or approaches, both conventional and unconventional?"
   - Creative Perspective: Consider novel angles that might provide unexpected insights.

   *2.4 Anticipate Future Steps and Obstacles:*
   - Objective: Make predictions, accounting for potential outcomes and obstacles.
   - Reflection: "What challenges might I face? Is my plan flexible for different scenarios?"
   - Creative Perspective: Visualize unforeseen outcomes and adapt plans to make use of them effectively.

   *2.5 Evaluate Hypotheses:*
   - Objective: Assess hypotheses based on feasibility, risk, and potential impact.
   - Evaluation: Refine Confidence and Creative Scores as needed.
   - Reflection: "Am I unbiased in my assessment? Which options fit best with the overall objectives?"
   - Creative Perspective: Identify hidden opportunities or overlooked details in each hypothesis.

   *2.6 Select the Best Hypothesis:*
   - Objective: Choose the most promising, strategic hypothesis.
   - Reflection: "Why does this hypothesis stand out? How does it uniquely address the issue?"
   - Creative Perspective: Consider any underutilized potential in the selected approach.

   *2.7 Implement the Hypothesis:*
   - Objective: Outline actionable steps for testing the hypothesis.
   - Reflection: "Is this plan practical? What resources or preparation are required?"
   - Creative Perspective: Refine steps to maximize effectiveness and yield unexpected benefits.

   *2.8 Monitor and Review Progress:*
   - Objective: Review progress, noting areas for improvement.
   - Reflection: "What’s working well? What could be improved?"
   - Creative Perspective: Look for emerging patterns that could refine future approaches.

   *2.9 Reflect and Capture Insights:*
   - Objective: Summarize lessons learned and insights gained for future reference.
   - Reflection: "What new understanding has emerged from this process?"
   - Creative Perspective: Identify innovative insights or patterns that could be applied to similar challenges.

3. *Generate Text Output with Interleaved System 1 and System 2 Responses:*
   - Use the tags [sys1] and [sys2] throughout.
   - Aim for a lengthier, detailed response. Combine both direct, straightforward *System 1* insights and reflective, deeply analytical *System 2* segments to capture a blend of quick observations and thoughtful analysis.

---

### *Example Input Text:*

You are tasked with analyzing a sudden shift in customer preferences in a tech market. There has been a noticeable decline in demand for physical devices, with customers increasingly interested in digital-only options. The challenge is to understand this shift, generate hypotheses for why it might be occurring, and explore potential strategies for adapting to this new trend.

---

### *Processed Output with System 1 and System 2 Thinking:*

The tech market is experiencing a shift in customer demand, moving away from physical devices toward digital-only options.

[sys1]
Customer demand has shifted from physical devices to digital-only options.
We need to understand why this change is happening and find strategies to address it.
Key factors may include cost, convenience, and technological trends.
[end sys1]

[sys2]
**2.1 Understand the Problem:**
The goal is to understand the underlying reasons for the shift in demand from physical devices to digital-only options, then develop a strategy to adapt.

*Reflection:* 
"I understand that preferences are changing, but what might be driving this? Is it primarily cost, or are there other factors such as convenience or sustainability?"

*Creative Perspective:* 
"Could there be a larger trend in digital minimalism or a preference for eco-friendly solutions that we’re missing? What unseen motivations might explain this shift?"

**2.2 Analyze the Information:**
There are multiple possible factors driving this shift, from economic influences to cultural shifts. It’s essential to isolate each factor and understand its impact.

*Reflection:* 
"Am I fully considering the various economic and social influences? Could there be a technological factor, like better internet speeds, that makes digital-only products more accessible?"

*Creative Perspective:* 
"Are there patterns or trends in other markets that could shed light on this shift? Could this be part of a larger trend toward virtual experiences?"

**2.3 Generate Hypotheses:**
1. Customers prefer digital options due to lower costs. (Confidence: 0.8, Creative: 0.4)
2. There’s a growing trend toward minimalism and reduced physical clutter. (Confidence: 0.7, Creative: 0.7)
3. Digital products offer greater flexibility and ease of use. (Confidence: 0.6, Creative: 0.6)
4. Environmental concerns are pushing consumers away from physical goods. (Confidence: 0.6, Creative: 0.8)
5. Advances in tech make digital-only options more functional. (Confidence: 0.8, Creative: 0.5)
6. Pandemic-era remote work increased demand for digital solutions. (Confidence: 0.7, Creative: 0.6)
7. Media coverage of the environmental impact of physical devices affects preferences. (Confidence: 0.5, Creative: 0.7)
8. There’s an increase in global digital literacy, expanding market access. (Confidence: 0.6, Creative: 0.6)
9. Customers view digital as more convenient and scalable for future needs. (Confidence: 0.7, Creative: 0.5)
10. Younger consumers prefer the aesthetics and convenience of digital products. (Confidence: 0.6, Creative: 0.6)

*Reflection:* 
"Have I considered all possible influences? Are there any surprising factors that could explain this shift?"

*Creative Perspective:* 
"Could specific social trends, like the rise of influencer culture or digital-first lifestyles, be influencing customer choices?"

**2.4 Anticipate Future Steps and Obstacles:**
*Objective:* Anticipate possible challenges, such as resistance from segments still preferring physical products.

*Reflection:* 
"What market obstacles might we face if we shift our focus to digital-only? Are there sub-segments that still prioritize physical products?"

*Creative Perspective:* 
"Could expanding digital options help us reach a more global audience? Are there emerging trends that we could leverage in our strategy?"

[end sys2]

[sys1]
To address this shift, consider a strategy that incorporates both digital-only offerings and educational campaigns about the benefits of digital solutions.
Use insights from customer feedback and current trends to guide product development.
Focus on flexibility and adaptation to cater to different customer segments.
[end sys1]


Introduction {#Sec1}
============

With advancing age, thermoregulatory defense mechanisms may be impaired. Recent studies indicate that even during mild cold exposure elderly are predisposed to risk of hypothermia (DeGroot and Kenney [@CR9]). Skin blood flow is a major effector of heat loss in humans, as it transports heat from the body core to the skin. DeGroot and Kenney ([@CR9]) report a reduced vasoconstrictor response in elderly subjects compared with young adults. However, their biophysical analysis could not explain why elderly failed to defend their core temperature. In his editorial response van Someren proposed (Van Someren [@CR35]) that there might be an underestimation in calculations of the actual heat loss, because the regions rich in arterio venous anastomoses (AVA) are generally not taken into account. AVAs are predominantly found in glabrous skin such as palms, fingers, soles, and forehead (Bergersen et al. [@CR3]; Donadio et al. [@CR10]; Gorgas et al. [@CR14]; Lenasi and Strucl [@CR25]). Together with their relatively large surface to volume ratio and high sensitivity to thermal changes (Defrin et al. [@CR8]), these locations are ideally adapted as heat exchangers with the environment (Grahn and Craig Heller [@CR15]; Grahn et al. [@CR16]; Van Someren [@CR35]). Hence, a blunted perfusion response in elderly in these skin areas might explain why elderly fail to maintain their core temperature when exposed to cold (Gilbert et al. [@CR13]). Clothing provides insulative protection to most of the body surface. Therefore, the initial defense to cold might be related to local cooling of exposed areas, which in fact are mainly glabrous skin sites (forehead and hands). Age effects on mechanisms of mediating local cold-induced vasoconstriction are well documented for non-glabrous human forearm skin, yet no information is available for glabrous (hand) skin.

Neurally mediated vasoconstriction works primarily through sympathetic adrenergic axon reflexes and alpha~2~-adrenergic receptors (Hodges et al. [@CR18]; Kellogg [@CR21]; Pergola et al. [@CR29]). However, in vitro research does not support findings of increased cold-related axonal release of sympathetic adrenergic agents (Johnson [@CR19]). Therefore, non-neural mechanisms are likely involved. Non-neural mechanisms include the rho-kinase pathway and removal of nitric oxide (Hodges et al. [@CR17]; Thompson-Torgerson et al. [@CR32]). Experimental evidence indicates that the early phase of vasoconstriction due to local cooling is mainly dependent on neural regulation and that late phase vasoconstriction relies more on non-neural mechanisms (Pergola et al. [@CR29]).

From literature it is known that during local cooling, young adults and elderly show a similar level of vasoconstriction at the ventral forearm (Thompson et al. [@CR30]; Thompson-Torgerson et al. [@CR33]). Interestingly, the actual mechanisms by which the vasoconstriction is mediated are different. Elderly show a reduced response to noradrenergic agents (Thompson et al. [@CR30]), yet this is compensated by an increased vasoconstriction through non-adrenergic mechanisms (Thompson-Torgerson et al. [@CR33]). It is unclear whether young and elderly show different vasoconstriction due to local cooling at other skin sites than the forearm, such as glabrous and non-glabrous skin of the hand. Many studies describe that innervation and topology of cutaneous microcirculation are not homogenous (Donadio et al. [@CR10]; Johnson et al. [@CR20]; Kellogg [@CR21]; Krogstad et al. [@CR24]; Wilson et al. [@CR37]; Yamazaki and Sone [@CR38]). For instance, glabrous skin (palms, fingers, soles, lips) is innervated mostly by sympathetic noradrenergic nerves and is rich in AVAs (Alvarez et al. [@CR1]; Charkoudian [@CR6]; Donadio et al. [@CR10]; Kellogg [@CR21]; Krogstad et al. [@CR24]). Studies by Ekenvall et al. have shown that vascular responses to local cooling and noradrenalin in human finger skin (glabrous) are primarily mediated through alpha~2~-adrenergic receptors (Ekenvall et al. [@CR12]; Lindblad et al. [@CR26]). In contrast to glabrous skin, non-glabrous skin has no AVAs and is innervated by both noradrenergic and cholinergic nerves (Kellogg [@CR21]).

In this study, we are interested in age-related differences in perfusion in response to cooling at the hand sites. No data on age effects on vasoconstriction due to local cooling at hand skin and mechanisms that mediate it are available in literature. Therefore, we tested the hypotheses that at hand sites (a) elderly show equal vasoconstriction due to local cooling and (b) elderly show reduced perfusion response to neuronal (nor-adrenergic) stimuli.

Methods {#Sec2}
=======

Ethical approval {#Sec3}
----------------

The medical ethical committee of Maastricht University Medical Center + approved the study. Each subject gave verbal and written informed consent prior to participation in the study. All procedures conformed to the standards of the Declaration of Helsinki.

Subjects {#Sec4}
--------

Sixteen young adults (18--28 years; 8 M, 8 F) and sixteen elderly (68--78 years, 8 M, 8 F) were included (characteristics in Table [1](#Tab1){ref-type="table"}). All subjects were healthy, non-obese, non-smokers, and not taking medications. All young females were tested during the early follicular phase of their menstrual cycle. Subjects refrained from caffeinated or alcoholic beverages in the morning prior to the test, but were allowed to eat a small breakfast.Table 1Selected subject characteristicsSubject characteristicsY (*n* = 16)E (*n* = 16)*P* valueAge (year)23.19 ± 0.7371.33 ± 0.61^\*^*P* \< 0.01Gender (Male/female)8/88/8Height (m)1.74 ± 0.021.67 ± 0.02^\*^*P* \< 0.04Mass (kg)64.36 ± 2.3265.77 ± 2.29N.S.BMI (kg/m^2^)21.25 ± 0.7323.42 ± 0.53^\*^*P* \< 0.01Systolic BP (mmHg)119.00 ± 2.69129.47 ± 3.63^\*^*P* \< 0.03Diastolic BP (mmHg)66.38 ± 1.1769.07 ± 2.28N.S.Mean BP (mmHg)83.92 ± 1.2489.20 ± 2.12^\*^*P* \< 0.04Mean skin temp. (°C)33.74 ± 0.0432.9°C ± 0.06^\*^P \< 0.01Whole body fat (%)22.48 ± 2.0027.40 ± 1.81N.S.Leisure activity level3.31 ± 0.123.55 ± 0.11N.S.Values are presented as mean ± SEM*Y* young adults, *E* elderly, *BP* blood pressure\** P* \< 0.05 versus young adult

Protocol {#Sec5}
--------

Because of increased sympathetic vascular tone in the morning (Panza et al. [@CR27]) experiments were conducted in the afternoon. After subjects were seated skin sites were cleaned with alcohol and air-dried. The studied skin sites were the dorsal side of the hand between the 2nd and 3rd metacarpal, the ventral hand at the base of the thumb, and the ventral forearm halfway the wrist and inner side of the elbow. To reduce the influence of age differences in systemic sympathetic adrenergic tone (Wilson et al. [@CR36]) bretylium tosylate (10 mM, Bio-Connect, the Netherlands), diluted in glycol propylene, was delivered via iontophoresis (PerIont, Sweden). Iontophoresis is a non-invasive method of delivering a drug through the skin using a small electric charge. Bretylium (BR) is a positively charged drug, which is propelled through the cutaneous barrier by the anode of the iontophoretic chamber. Glycol propylene was chosen as a carrier as it is non-conducting by itself; hence it does not interfere with the drug delivery (Kellogg et al. [@CR22]). Bretylium is known to selectively block local endogenous release of noradrenergic neurotransmitters (Kellogg et al. [@CR22]). Because of inherent differences in skin permeability between glabrous and non-glabrous skin, iontophoretic characteristics were modified between sites to deliver a dose that caused a similar physiologic effect. Aging per se may affect the cutaneous barrier properties (Carmeli et al. [@CR4]). Thus, the iontophoresis dose scheme was set at a level to be maximally effective for both groups. From literature (Johnson et al. [@CR20]; Kellogg et al. [@CR22]; Pergola et al. [@CR29]; Yamazaki and Sone [@CR38]) and a pilot study it was concluded that for effective bretylium treatment, different duration and current strength of iontophoresis was needed for different sites, as shown in Table [2](#Tab2){ref-type="table"}. Control measurements (BR−) of perfusion response to local cooling were performed ipsilateral to the locations treated with bretylium (BR+). After iontophoresis of bretylium, sites were given 1 h for hyperemia to subside and sympathetic blocking to take effect. Skin temperature was measured in 1 min intervals using iButtons (type DS1921H; Maxim/Dallas Semiconductor Corp., USA) (van Marken Lichtenbelt et al. [@CR34]) at the 14 positions of the adapted Mitchel/Wyndham equation for mean skin temperature (Choi et al. [@CR7]). Next, subjects were dressed in a water-perfused suit (TUBEsuit, DTI) to control whole body skin temperature (Blanketrol II, Cincinnati Sub-zero). The effectiveness of the bretylium treatment was tested via whole body cooling by setting the temperature of the water perfused suit to 26°C. Whole body cooling elicits reflex vasoconstriction through release of noradrenalin and cotransmitters from sympathetic nerve terminals; effective blockade of presynaptic nerve terminals abolishes the response, while at non-treated sites perfusion drops (Kellogg et al. [@CR22]). During the rest of the experiment, subjects remained in thermal comfort by perfusing the suit with water at 33°C (Parsons [@CR28]). Room temperature was kept at 24°C. Laser Doppler flowmetry (Perimed PF5000, Sweden) was used for measurement of skin perfusion. Custom-made Peltier elements in the casing of the probes allowed for local temperature control of skin sites at 24°C and 33°C. Measurements were divided into three phases (see Fig. [1](#Fig1){ref-type="fig"}). After a 30 min baseline period at 33°C, skin sites were cooled to 24°C (5°C/min) for 15 min, until perfusion reached a nadir. Next noradrenalin, diluted in glycol propylene (Bio-Connect, the Netherlands), was delivered transcutaneously via iontophoresis to simulate maximal response to noradrenergic stimulation (details in Table [2](#Tab2){ref-type="table"}, example recording in Fig. [2](#Fig2){ref-type="fig"}).Table 2Current and duration of iontophoresis (0.5 cm^2^) and concentration of drugs at treated skin sitesIontophoresis properties at treated skin sitesCurrent (mA)*t* (min)Concentration (mM)Bretylium Dorsal hand0.241510 Ventral hand0.302510 Ventral forearm0.241010Noradrenalin Dorsal hand0.2412.5 Ventral hand0.3055.0 Ventral forearm0.2412.5Fig. 1Timeline of measure protocol repeated at each skin site. Blood pressure was measured at start of baseline and at end of noradrenalin phaseFig. 2Individual recording of skin perfusion. Local skin temperature was 33°C during baseline, 24°C during cooling and administration of noradrenalin

At control sites (BR−) noradrenalin was delivered to a subset of subjects only (young: *n* = 11 and elderly: *n* = 13).

A study by Thompson (Thompson et al. [@CR30]) has shown that local cooling of skin and local administration of NA does not alter mean arterial pressure (MAP). Therefore, and to minimize the influence of the blood pressure (BP) measurement itself to the perfusion, BP measurement was restricted to before baseline and after administration of noradrenalin via digital blood pressure monitoring (CRESTA, Taiwan). Cutaneous vascular conductance (CVC) was calculated as perfusion divided by mean arterial pressure (MAP = 1/3 systolic BP + 2/3 diastolic BP). Whole body fat percentage was measured through Dual-X-ray Absorptiometry (DXA, HOLOGIC, USA). Daily leisure activity of subjects was measured through a Baecke (Baecke et al. [@CR2]) questionnaire.

Data analysis {#Sec6}
-------------

Perfusion data was sampled at 8 Hz. Baseline values of CVC were obtained by averaging 3 min of perfusion data at baseline. Vasoconstriction measures were obtained by averaging 3 min during local cooling or after administration of noradrenalin. Data for local cooling alone were normalized to baseline; total vasoconstriction response (local cooling + NA) was normalized to baseline. SPSS16.0 for Mac was used for statistics. Subject characteristics were tested for differences via Student-t testing. A MANOVA was used to test for differences in %ΔCVC among age and gender groups. Data were presented as mean ± SEM unless stated otherwise. Statistical significance level was set at *P* \< 0.05.

Results {#Sec7}
=======

Elderly subjects differed significantly from young adult subjects in BMI, baseline mean arterial pressure (MAP) and mean skin temperature (*P* \< 0.05) (Table [1](#Tab1){ref-type="table"}). Since no significant gender differences were evident, data of both males and females were pooled. Daily leisure activity did not differ significantly between both age groups. Because BMI, baseline MAP, and mean skin temperature showed no significant relation to vasoconstriction measures and leisure activity was equal over age groups, we assumed that observed effects were mainly related to age. Due to technical malfunction during iontophoresis, testing on *n* = 3 young adults and *n* = 1 elderly was aborted.

To test the effectiveness of the bretylium treatment, whole body rapid cooling was applied. This resulted in a decrease of perfusion units (PU) at control sites, but not at bretylium-treated sites for both age groups: (young control −73 ± 4%; young bretylium −8 ± 6%; elderly control −65 ± 4%; elderly bretylium −5% ± 3%).

At bretylium-treated sites baseline CVC values did not differ significantly between age groups. Control sites also showed no age effect except for the ventral hand (young adults 0.66 ± 0.12 PU/mmHg vs. elderly 0.31 ± 0.04 PU/mmHg; *P* \< 0.02).

Non-noradrenalin treated skin sites {#Sec8}
-----------------------------------

Bretylium-treated sites at the ventral forearm and dorsal side of the hand (non-glabrous skin) showed a significantly smaller percentage change in CVC due to local cooling than non-treated sites (see Table [3](#Tab3){ref-type="table"}). At the glabrous skin site (ventral hand) vasoconstriction to local cooling at BR+ sites was not significantly different than vasoconstriction at BR− sites, indicating that local mechanisms dominated. At bretylium-treated sites no significant age effect to local cooling was found. At control sites (BR−), only the ventral forearm showed reduced vasoconstriction in elderly (*P* \< 0.05).Table 3Change in skin perfusion due to local cooling (in % from baseline) at the ventral forearm, dorsal hand, and ventral handVasoconstriction to local cooling and noradrenalinBR+ NA−BR−NA−BR+ NA+BR−NA+Ventral forearm Young adults−22 ± 7−46 ± 5\*−76 ± 3\*−57 ± 6^\#^ Elderly−14 ± 4−33 ± 3\*−60 ± 5\*−45 ± 4^\#^ Age effectN.S.*P* \< 0.05*P* \< 0.05N.S. (*P* \< 0.07)Dorsal hand Young adults−32 ± 5−49 ± 6\*−74 ± 4\*−71 ± 4 Elderly−27 ± 5−45 ± 5\*−72 ± 4\*−65 ± 3 Age effectN.S.N.S.N.S.N.S.Ventral hand Young adults−35 ± 14−49 ± 6−80 ± 7\*−63 ± 3 Elderly−37 ± 11−59 ± 5−70 ± 11\*−67 ± 5 Age effectN.S.N.S.N.S.N.S.*BR*− Control site (no bretylium), *BR*+ bretylium-treated skin, *NA−* before local administration of noradrenalin, *NA*+ after local administration of noradrenalin\* Significant difference in vasoconstriction compared with BR+ NA− (*P* \< 0.05)^\#^Significant difference in vasoconstriction compared with BR+ NA+ (*P* \< 0.05)

Noradrenalin-treated skin sites {#Sec9}
-------------------------------

After iontophoresis of a supra-physiological dose of noradrenalin perfusion decreased significantly at all measurement sites (Table [2](#Tab2){ref-type="table"}). The change in CVC was significantly smaller in elderly as compared with young adults at the bretylium-treated sites of the ventral forearm (*P* \< 0.01), indicating a reduced response to noradrenalin in elderly. However, at the ventral and dorsal sides of the hand no significant age effect was found. The effect of noradrenalin at control (BR−) compared with bretylium-treated (BR+) sites was not significantly different at the hand sites, but lower at the ventral forearm (*P* \< 0.05).

Discussion {#Sec10}
==========

This study explored age effects in vasoconstriction during local cooling at three different sites of the skin. For the first time, the dorsal and ventral sides of the hand were measured, in addition to the ventral forearm that is traditionally studied. The primary findings of this study areThere was no significant age effect on vasoconstrictor response to local cooling at both glabrous and non-glabrous skin of the hand.In contrast to the results from the ventral forearm skin, elderly did not show a blunted response to noradrenalin during local cooling at hand skin sites. This indicates that at hand skin the noradrenergic mechanism of vasoconstriction is maintained with age.

Ventral forearm {#Sec11}
---------------

Studies by Thompson et al. (Thompson et al. [@CR30]; Thompson-Torgerson et al. [@CR33]) have shown that at the ventral forearm vasoconstrictor response to local cooling is not different between young adults and elderly. Yet the mechanisms that mediate vasoconstriction are different. Elderly have a decreased noradrenergic vasoconstriction response, which is compensated by increased vasoconstriction through local mechanisms. In the present study, however, we observed a blunted vasoconstriction in elderly to local cooling at the control skin site (*P* \< 0.05). On the other hand, our observation that the neural (noradrenergic) response is reduced in elderly was in line with earlier studies that also indicate reduced sensitivity to noradrenalin at the ventral forearm (Thompson et al. [@CR30], [@CR31]). This was strengthened by the result that the vasoconstriction response of noradrenalin at bretylium-treated skin (BR+ NA+), was significantly smaller in the elderly.

At ventral forearm skin that had sympathetic blockade (BR+), we observed no age effect in vasoconstriction to local cooling. This indicates that the elderly did not show increased vasoconstriction through local mechanisms.

Dorsal hand {#Sec12}
-----------

The dorsal hand (non-glabrous skin) showed no age effect of vasoconstriction to local cooling at both bretylium-treated and control sites. Even the application of exogenous noradrenalin did not result in an age effect. Both in young adults and elderly, the bretylium-treated skin sites showed a significantly smaller vasoconstrictor effect to local cooling alone than the control site. This indicates that at the dorsal hand, similar to the ventral forearm, vasoconstriction during early phase local cooling was obtained through noradrenergic and non-adrenergic pathways. In combination with the absence of an age effect during local cooling alone at the control site, this indicates that aging per se does not alter noradrenergic sensitivity. This was strengthened by the results that no age effect is found after administration of noradrenalin (BR+ NA+).

Ventral hand {#Sec13}
------------

The ventral hand, like the dorsal hand, showed no age effect of vasoconstriction either to local cooling or to vasoconstriction after administration of noradrenalin. Glabrous skin consists of capillaries and arterio-venous anastomoses (AVA). Non-glabrous skin only has capillaries. These AVAs, which are solely innervated by sympathetic adrenergic nerves, are capable of shunting blood directly from the arteriole to the venous bed, thereby bypassing the capillaries and drastically reducing cutaneous blood flow (Kellogg [@CR21]). Suprisingly, despite greater sympathetic innervation at glabrous skin sites (Defrin et al. [@CR8]) no significant difference in vasoconstriction was observed between the BR+ and BR− site during local cooling. This indicates that at the ventral hand, vasoconstriction by local mechanisms was able to compensate for lack of vasoconstriction by noradrenergic mechanisms. An interesting parallel may be drawn with another study by Wilson et al. ([@CR37]), who found that glabrous skin with sympathetic blockade was still able to autoregulate flow during blood pressure variations, whereas non-glabrous skin lost its capability of autoregulation.

From a functional perspective of thermoregulation, the ventral side of the hand, as compared with the dorsal side and the ventral forearm, is most adapted as a heat exchanger through the abundance of AVAs (DeGroot and Kenney [@CR9]; Grahn et al. [@CR16]; Van Someren [@CR35]) and high sensitivity to temperature changes (Defrin et al. [@CR8]). Various studies underscore the importance of glabrous skin areas (Gilbert et al. [@CR13]; Grahn and Craig Heller [@CR15]; Krauchi and Wirz-Justice [@CR23]). Therefore, maintaining the functionality as heat exchanger of these skin areas is more important than, for instance, at the less exposed forearm. Analogous to the beneficial effects of physical exercise on vascular reactivity (Lenasi and Strucl [@CR25]), naturally occurring exposure to cold of the hands might keep the skin of elderly "fit" to respond to daily changes in environmental temperatures.

Limitations {#Sec14}
-----------

Other studies on local regulation of skin perfusion cited in this article in general used 34°C for baseline whole body mean skin temperature and local skin temperature. Although we used bretylium to avoid effects of systemic sympathetic tone, this may still have influenced results on non-treated sites. Furthermore, relatively fit and healthy elderly were selected. Despite age in years was indicative of senescence, the biological age could have been much younger. Therefore, subject selection based on biological age would make sense. Yet, the difficulty remains how to define the biological age. Since the majority of elderly in western societies are taking drugs that affect blood pressure (69.6% of aged over 65 years in the Netherlands (CBS [@CR5])), it may be interesting to study whether these elderly, whose biological age might better reflect their age in years, do show a greater effect of age in vascular responses. Furthermore, the delivery of drugs through iontophoresis might induce a vasodilator response, by stimulating c-fibers, which has to be overcome before actual vasoconstriction is measured (Drummond and Lipnicki [@CR11]). In this study, no age effect was found for the small iontophoretic vasodilation at any of the measured locations. Furthermore, despite differences in protocols, vasoconstriction values found in our study matched that of Thompson et al. (Thompson et al. [@CR30]) with respect to vasoconstrictor response to noradrenalin imposed on local cooling.

Summary {#Sec15}
=======

In summary, there was no significant age effect on vasoconstrictor response to local cooling at both glabrous and non-glabrous skin of the hand. This is in line with the results from earlier studies on the ventral forearm. Contrary to earlier studies, elderly did not show a blunted response to noradrenalin during local cooling. This indicates that at hand skin sites the noradrenergic (neural) mechanism of vasoconstriction is maintained with age.

Conclusion {#Sec16}
==========

In contrast to the results from literature covering ventral forearm studies, our study on hand skin sites shows that upon cooling both local (non-neural) and noradrenergic (neural) mechanisms of vasoconstriction are maintained in the elderly.

This study was supported by SenterNovem, The Netherlands.

**Conflict of interest statement** None.

**Open Access** This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.

[^1]: Communicated by Narihiko Kondo.