Effect of ageing on tactile transduction processes

Ageing Research Reviews 13 (2014) 90–99

Contents lists available at ScienceDirect

Ageing Research Reviews journal homepage: www.elsevier.com/locate/arr

Review

Effect of ageing on tactile transduction processes Johanna Decorps a,b , Jean Louis Saumet a,b , Pascal Sommer a,b , Dominique Sigaudo-Roussel a,b , Berengere Fromy a,b,∗ a b

Laboratory of Tissue Biology and Therapeutic Engineering, Centre National de la Recherche Scientifique (CNRS) UMR 5305, Lyon, France University of Lyon 1, UMR 5305, Lyon, France

a r t i c l e

i n f o

Article history: Received 22 May 2013 Received in revised form 2 December 2013 Accepted 16 December 2013 Available online 26 December 2013 Keywords: Animal models Mechanosensitivity Microcirculation Sensory fibres Skin Touch

a b s t r a c t With advancing age, a decline in the main sensory modalities including touch sensation and perception is well reported to occur. This review mainly outlines the peripheral components of touch perception highlighting ageing influences on morphological and functional features of cutaneous mechanical transducers and mechanosensitive ion channels, sensory innervation, neurotransmitters and even vascular system required to ensure efferent function of the afferent nerve fibres in the skin. This, in conjunction with effect of ageing on the skin per se and central nervous system, could explain the tactile deficit seen among the ageing population. We also discuss appropriate tools and experimental models available to study the age-related tactile decline. © 2013 Elsevier B.V. All rights reserved.

Contents 1. 2.

3.

4.

5.

6.

7.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Effect of ageing on the cutaneous mechanical transducers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Histologically distinct transducers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Ion channels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Effect of ageing on the peripheral nervous system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Sensory detection thresholds (functional studies) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Nerve conduction velocities and structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Nerve fibre density . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Effect of ageing on the efferent function and the neuropeptides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Neurovascular interaction in the skin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Neurovascular interaction triggered by tactile stimulation: pressure-induced vasodilation (PIV) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Other relevant effects of ageing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Structural changes of the skin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Higher brain structures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Experimental models for ageing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1. Non mammalian models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2. Mouse models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3. Rat models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

∗ Corresponding author at: Laboratory of Tissue Biology and Therapeutic Engineering, UMR CNRS 5305, 7 Passage du Vercors, F-69367 Lyon cedex 07, France. Tel.: +33 478 778662; fax: +33 478 785769. E-mail addresses: [email protected] (J. Decorps), [email protected] (J.L. Saumet), [email protected] (P. Sommer), [email protected] (D. Sigaudo-Roussel), [email protected] (B. Fromy). 1568-1637/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.arr.2013.12.003

91 91 91 91 91 92 92 93 93 93 94 94 94 94 94 95 95 95 96 96

J. Decorps et al. / Ageing Research Reviews 13 (2014) 90–99

1. Introduction Ageing is associated with reductions of up to 50–60% in the principal functions of the skin, including protection, excretion, secretion, absorption, thermoregulation, pigmentogenesis, regulation of immunological processes and wound repair. Ageing is also associated with a progressive decline in cutaneous sensory perception reported for many of the senses (Guergova and Dufour, 2011; Lin et al., 2005; Taguchi et al., 2010), including the mechanosensitivity (Thornbury and Mistretta, 1981; Wickremaratchi and Llewelyn, 2006; Woodward, 1993; Wu et al., 2011). The sense of touch is composed of many systems previously described in excellent reviews (Arnadottir and Chalfie, 2010; Chalfie, 2009; Lumpkin et al., 2010; Roudaut et al., 2012). Briefly, the tactile sensation relies on the afferent function relaying the sensory information from the skin to the central nervous system, involving the cutaneous transducers detecting mechanical stimuli and the transmission of the sensory stimuli to higher brain structures, as well as the efferent function of the sensory nerve fibres by secreting neurotransmitters in the skin requiring an intact neurovascular communication (Fromy et al., 2008). The perceptual decline of the cutaneous functions is regarded as a typical signature of the intrinsic physiological, structural, and metabolic changes that occur during ageing (Cerimele et al., 1990; Farage et al., 2008; Fenske and Lober, 1986). The intrinsic rate of skin ageing in any individual can also be dramatically influenced by personal and environmental factors, such as diet, exercise, psychosocial factors and the amount of exposure to ultraviolet light (Thurstan et al., 2012). Within the category of normal ageing, a distinction can be made between usual ageing, in which extrinsic factors heighten the effects of intrinsic ageing, and successful ageing, in which extrinsic factors play a neutral or positive role (Rowe and Kahn, 1987). This review describes the skin ageing focused on the structures involved in the different phases involved in the tactile perception (Fig. 1), as well as the appropriate assessment methods and some experimental models to study the age-related tactile defect.

2. Effect of ageing on the cutaneous mechanical transducers 2.1. Histologically distinct transducers The tactile ability of the skin results in part from the presence of distinct cutaneous sensory structures, including Merkel cells, Ruffini organs, Meissner and Pacinian corpuscles innervated by large myelinated A␤ fibres, and free nerve endings (Fromy et al., 2008; Johnson, 2001; Lumpkin et al., 2010; Roudaut et al., 2012) (Fig. 2, left panel). Pacini and Meissner corpuscles decrease in number and have a structural deterioration with ageing (Bolton et al., 1966; Cauna and Mannan, 1958; Gescheider et al., 1994; Stevens and Patterson, 1995) illustrated by histological evidence (Bolton et al., 1966; Mathewson and Nava, 1985; Pare et al., 2007; Vega et al., 2009). These structural changes in the periphery are correlated with declining tactile sensibility, as shown by a reduction in the sensitivity to the vibration (Cerimele et al., 1990; Perry, 2006; Verrillo et al., 2002) and touch (Stevens and Patterson, 1995), respectively. A deterioration of the discs of Merkel was also observed with ageing in rats (Baumann et al., 1986; Fundin et al., 1997), while it seems that the Merkel-neurite complexes are less affected (Bolton et al., 1966; Mathewson and Nava, 1985; Pare et al., 2007; Vega et al., 2009). A decline in the number of Ruffini corpuscles was reported in ligaments in elderly subjects (Morisawa, 1998) and rabbits (Aydog et al., 2006), as well as irregular and flattened margins (Aydog et al., 2006). Although the age-related changes on

91

Ruffini corpuscles are not clearly described in the skin, it is known that the proportion between mechanoreceptors with slow adaptation (Merkel cells and Ruffini corpuscles) and those with fast adaptation (Pacini and Meissner corpuscles) vary with ageing for the benefit of mechanoreceptors with fast adaptation (Reinke and Dinse, 1996). In addition to fast-conducting myelinated afferent fibres, there is a system of slow-conducting unmyelinated (C) afferents that respond vigorously to innocuous skin deformation (Vallbo et al., 1993, 1999; Zotterman, 1939), suggesting that these afferents may contribute to tactile sensation. Generally a distinction is made between the properties of fast conducting myelinated afferents and those of slowly conducting unmyelinated afferents, with the former subserving a sensory-discriminative role, and the latter an affective-motivational one, as previously reviewed (McGlone and Reilly, 2010; Olausson et al., 2010). However the contribution of C tactile afferents has never been reported within the age-related tactile deficit.

2.2. Ion channels The activation of the mechanosensitive ion channels is at the origin of the detection of low or high threshold mechanical stimuli required for the transduction to electrical signals in sensory neurons. Among them, transient receptor potential (TRP) channels (such as TRPA1) and degenerin/epithelial Na+ (DEG/ENaC) channels including acid-sensing ion channels (such as Asic2, Asic3), MEC4/MEC-10 and two-pore domain potassium (K+ )-selective channels (such as TREK1 and TRAAK) have been previously reviewed (Chalfie, 2009; Lumpkin et al., 2010; Nilius and Honore, 2012; Roudaut et al., 2012; Sherwood et al., 2012). Electrophysiological studies showed that the piezos, essential components of distinct stretch-activated ion channels (SACs), are also involved in the mechanotransduction (Coste et al., 2012), in particular in mechanosensory nociception in Drosophila (Kim et al., 2012). In humans and rodents, it has been shown that Asic3 channel, in addition to detect some cutaneous touch and painful stimuli, is needed for the adequate adjustment of the microcirculation in the skin in response to pressures (Fromy et al., 2012) playing as a neuronal mechanosensitive channel, while it is controversial (Arnadottir and Chalfie, 2010). Although the ageing effects on the structure and/or the function of these mechanosensitive ion channels are not described, one can speculate that they could contribute to the age-related tactile defect.

3. Effect of ageing on the peripheral nervous system In addition to the morphological changes in the peripheral receptors (described in paragraph 2), other abnormalities of the sensory system (detection thresholds, nerve conduction velocities, structural changes of sensory fibres, nerve fibre density) develop because of ageing. These influences are also considered to be involved in the augmentation of tactile sensation thresholds (attenuation of sensation and sensitivity) in the elderly. Indeed once the information is detected by the mechanoreceptors in the skin, this information is transferred from the periphery (the skin) to the central nervous system via the afferent nervous fibres, including the large myelinated afferents A␤-fibres, but also the small myelinated A␦- and unmyelinated C-fibres (Cole et al., 2006). To evaluate the effects of ageing on the peripheral sensory function, quantitative sensory testing (QST), motor and sensory nerve conduction velocities, microneurography and biopsies are mainly used in both humans and animals (Gibbons et al., 2006; Namer et al., 2009; Selim et al., 2010; Verdu et al., 1996, 2000).

92

J. Decorps et al. / Ageing Research Reviews 13 (2014) 90–99

PHASES

STRUCTURES

TECHNIQUES

Mechanical transducers Mechanosensitive ion channels

Immunohistochemical techniques

Signal propagation

Afferent nervous fibres

Signal integration

Higher brain structures

Functional studies (QST, spatial discrimination) Electrophysiological studies (MNCV, SNCV) Microneurography Immunohistochemical techniques

Tactile detection

Signal transduction

Sensory conduction

Efferent response Release neurotransmitters

Vascular response

Peptidergic sensory fibres

Skin microvessels (endothelial and vascular smooth muscular cells)

Immunohistochemical techniques Western Blot Vascular studies (in vivo, in vitro) Neurovascular interaction assessment (laser Doppler flowmetry)

Fig. 1. A simplified schematic of the tactile transduction processes. The mechanotransductive responses consist of three distinct phases: tactile detection, sensory conduction and efferent response.

3.1. Sensory detection thresholds (functional studies) Briefly, the QST method permits to determine detection thresholds to sensory stimuli, including touch, vibration, mechanical pain and heat. It is generally agreed that sensitivities to vibration and tactile stimulation assess the function of large myelinated fibres, whereas the cool and warm detection thresholds assess the function of small myelinated A␦ fibres and unmyelinated C fibres, respectively (Campero et al., 1996; Verdugo and Ochoa, 1992). Detection thresholds were generally independent of gender, whereas pain thresholds were significantly lower in women than men (Rolke et al., 2006). With ageing, mechanical detection thresholds are increased for touch, vibration and pressure in elderly subjects (Fromy et al., 2010; Gescheider et al., 1994; Rolke et al., 2006; Thornbury and Mistretta, 1981; Verrillo et al., 2002) and aged rats (personal observations), whereas mechanical sensitivity was increasing with age in the LOU/c strain (Alliot et al., 2002). The older subjects clinically diagnosed as non-neuropathic (using neuropathy symptom scores and routine clinical tests) displayed increased warm detection threshold compared to young adults, showing modest functional abnormality of small sensory fibres only (Fromy et al., 2010). In contrast, the neuropathic older subjects had much more severe sensory deficit in all modalities, showing functional abnormality of both small and large sensory fibres (Fromy et al., 2010). Consistently, some age-related abnormalities in small diameter fibres were previously reported earlier or more markedly than those in myelinated fibres (Pare et al., 2007; Ceballos et al., 1999). Altogether these studies support that ageing usually induces a slowly progressive sensory loss that affects first the small nerve fibres. Other functional studies of touch conveyed by cutaneous mechanoreceptors in glabrous skin found that the tactile spatial two-point discrimination performance decreases in elderly subjects, indicating a marked degradation of tactile spatial acuity with increasing age (Kalisch et al., 2009; Leveque et al., 2000; Stevens and Patterson, 1995). Similarly, bump detection thresholds (used to

evaluate tactile detection of small raised dots (bumps) on a smooth surface (LaMotte and Whitehouse, 1986)) was slightly increased in older control subjects (again emphasized by peripheral neuropathy) and was related to a decreased Meissner corpuscle density (Kennedy et al., 2011). However, various parameters can affect the results of these functional studies of touch, such as several characteristics of the stimuli, how the stimuli are applied, the subjective nature of the patient’s response and of the examiner’s interpretation, the degree of alertness of both participants or the anxiety of the animal. These various parameters can mask true sensitivity and induce erroneous conclusions. As a consequence, these methods permit to detect large differences (as observed in neuropathic patients) but is less reliable for the small changes (Selim et al., 2010). 3.2. Nerve conduction velocities and structure The electrophysiological studies found lower nerve conduction velocity values in older subjects (Di Iorio et al., 2006; Verdu et al., 2000) and animals (Verdu et al., 1996), particularly in myelinated fibres (Bouche et al., 1993; Verdu et al., 2000) due to their vulnerable myelin sheath (Peters, 2002; Verdu et al., 2000). The reduction of the myelin thickness observed in the peripheral nerves, together with changes in myelin structure, may be attributable to a decrease in the expression of the major myelin proteins (protein zero, peripheral myelin protein 22 and myelin basic protein) (Melcangi et al., 1998, 2000) and altered myelinogenesis (Verdu et al., 2000). The reduced nerve conduction velocities with advancing age could be also explained by decrease of axon diameter than of fibre diameter (Chase et al., 1992) increasing irregular shapes in transverse nerve sections, axonal degeneration and an increase in endoneurial collagen as reported in human sural nerve (Jacobs and Love, 1985), a loss of myelinated fibres and unmyelinated axons in tibial nerve of mice surviving more than 27 months (Ceballos et al., 1999). In contrast, no obvious correlation was seen between the density of unmyelinated axons and the age in human and rat sural nerves by

J. Decorps et al. / Ageing Research Reviews 13 (2014) 90–99

Fig. 2. Skin changes with ageing. The density of free nerve endings, Meissner and Pacini corpuscles are decreased with ageing whereas those of Merkel-neurite complexes and Ruffini organs seem less affected, resulting in age-related tactile defect. The morphology of the microvascular network also changes with ageing: decrease of capillary density and diameter, surface area and increase of tortuosity. The vascular capacities of vasodilatation in response to capsaicin (represented with red arrow) or to mechanical stimuli are altered with ageing, reflecting an age-related deficit of the neurovascular interaction (represented with black arrow). The structure of skin undergoes profound changes with ageing: dermal collagen, elastic fibres and glycosaminoglycans (visualized with blue line, green line and red complex respectively) are decreased, resulting in a loss of skin elasticity and firmness. These changes are associated with a decrease of thickness of epidermis and development of wrinkles with age.

others (Kanda et al., 1991). In addition, reorganization of voltagesensitive sodium channels in the axonal membrane (Adinolfi et al., 1991), reduced sodium–potassium pump activity (Namer et al., 2009), metabolic changes (such as decline of endoneurial ATP and creatine phosphate levels) and reduction of endoneurial blood flow likely contribute to impaired nerve conduction (Kihara et al., 1991; Verdu et al., 2000). The microneurography has also shown a more pronounced activity-dependent slowing of afferent C-fibre conduction in aged subjects (Namer et al., 2009). Predominantly, the mechanoresponsive C-fibres of aged subjects showed more slowing to high frequency stimulation (3 min, 2 Hz). The ratio of mechanoresponsive fibres to mechano-insensitive fibres was shifted in favour of the mechano-insensitive fibres in older subjects (Namer et al., 2009; Orstavik et al., 2006), particularly accentuated in patients suffering from painful diabetic neuropathy (Orstavik et al., 2006). This trend of a change in the C-fibre population with ageing towards a higher incidence of mechano-insensitive fibres relative to mechano-responsive fibres could in part explain the lower detection thresholds to mechanical stimuli with ageing. However the microneurographic experiments can only reveal changes in the ratio of fibre classes but do not provide information on the absolute number of peripheral nerve fibres. 3.3. Nerve fibre density The intra-epidermal nerve fibres can be visualized in skin biopsies with immunohistochemical techniques using the panaxonal marker anti-protein gene product 9.5 (PGP 9.5) as well as antibodies against specific components of the cytoskeleton

93

(e.g. neurofilaments and microtubules) and the myelin (e.g. myelin basic protein, peripheral myelin protein 22, and myelin-associated glycoprotein) in order to discriminate between myelinated and unmyelinated nerve fibres. In addition, based on their peptidergic content, the unmyelinated C fibres can be classified into two general populations, the non-peptidergic isolectin B4 positive (IB4+) and the peptide-containing IB4 negative (IB4−) subtypes. The established immuno-markers of unmyelinated nociceptors, such as substance P (SP) and calcitonin gene-related peptide (CGRP) are thus useful tools for distinguishing different subsets of sensory nerve fibres (Dalsgaard et al., 1989; McCarthy et al., 1995; Sommer and Lauria, 2007; Wang et al., 1990). Using these techniques, it was reported that ageing induces a decrease in the epidermal innervations of the facial skin (Besne et al., 2002), the trunk (Lauria et al., 1999), the forearms (Chang et al., 2004), whereas epidermal innervation in skin from the abdomen was unchanged and even increased in mammary skin (Besne et al., 2002). At the distal leg and feet, it is generally admitted that intra-epidermal nerve fibre density gradually declines with increasing age (Chang et al., 2004; Goransson et al., 2004; Lauria et al., 2010; Panoutsopoulou et al., 2009), even though little effect of ageing on the density and spatial pattern of epidermal innervation was also reported (Lauria et al., 1999). Correlated with both the presence and the severity of sensory neuropathies (Holland et al., 1997; McCarthy et al., 1995) intra-epidermal nerve fibre density has thus emerged as a marker of neuropathy progression appearing particularly efficient to identify small fibre sensory neuropathies (Herrmann et al., 1999). Using the blister technique to separate the epidermis from the dermis at the junction between the two and computerized image analysis after immunostaining the whole disc of epidermis (Kennedy et al., 1999), it was also shown that the density of epidermal nerve fibres was lower for older subjects at the foot and calf level (Panoutsopoulou et al., 2009), showing no systematic differences of epidermal nerve fibre density between skin blisters and biopsies. All these functional and morphological changes of the peripheral nervous system are presumably related to the age-related decreases in tactile perception, even though some studies reported no correlation between quantitative sensory testing parameters and intra-epidermal nerve-fibre density (Holland et al., 1997; Periquet et al., 1999).

4. Effect of ageing on the efferent function and the neuropeptides 4.1. Neurovascular interaction in the skin The peptidergic afferent sensory nerves have an efferent function and stimulate target tissues by secreting neurotransmitters (Misery, 1997). Since the seminal studies of Lewis in the 1920s, it has been well established that transmitters released following the passage of antidromic impulses down sensory nerve collaterals during “axon reflex” activity produce vasodilation of skin vessels (Fig. 2, middle panel). Understanding of the interaction between the vascular and nervous systems need to be thought of as an overall working unit rather than separated systems. The assessment of nerve-related vasodilation has been thus proposed as an alternative method to quantify the efferent function of sensory nerve fibres (Parkhouse and Le Quesne, 1988). Different techniques measure different aspects of the circulation, including physical movement of red blood cells (radionuclide, ultrasound and laser Doppler techniques, capillary microscopy), heat transport (thermometry, thermographic imaging, thermal clearance) and oxygen content (transcutaneous oxygen measurement) (De Backer et al., 2010; Roustit and Cracowski, 2012). Among them, the non-invasive exploration of cutaneous microcirculation have been mainly based

94

J. Decorps et al. / Ageing Research Reviews 13 (2014) 90–99

on laser Doppler flowmetry given a measure of the integrated motion of red cells in many small vessels within the measuring volume, irrespective of the direction of cell movement. In this context, the activation of sensory fibres is usually performed by different noxious stimuli (intradermal electrical stimulation, local heating to 44 ◦ C) or experimentally by capsaicin. Some human thermoregulatory studies report diminished local sensory axon reflex-mediated vasodilation during body or local heating and exercise with ageing (Kenney et al., 1997; Minson et al., 2002; Tew et al., 2011). In total accordance, there is a deterioration of capsaicin-sensitive primary afferent function in aged skin, illustrated by a reduction of local skin blood flow in response to capsaicin in older subjects (Helme and McKernan, 1986; Munce and Kenney, 2003). Therefore a reduced vasodilation can indicate a functional deficit of the neurovascular interaction, but will not appear appropriate for testing tactile defect if the sensory fibre activation is not triggered by mechanical stimulation. 4.2. Neurovascular interaction triggered by tactile stimulation: pressure-induced vasodilation (PIV) In young healthy skin, the local application of an innocuous pressure leads to an increase of skin blood flow that relies on an intact endothelium and neurovascular interaction, as reported in humans (Fromy et al., 1998) and rodents (Demiot et al., 2006; Fizanne et al., 2004; Fromy et al., 2000, 2012; Garry et al., 2007; Sigaudo-Roussel et al., 2004). Therefore the assessment of the pressure-induced vasodilation (PIV) appears particularly appropriate to test the cutaneous neurovascular interaction involved in the touch transduction. As expected, PIV is impaired by ageing indicating a defective neurovascular communication in mice and humans (Fromy et al., 2010; Gaubert et al., 2007). Relying on sensory nerve function and vascular capacities, PIV reduction could be explained by an endothelial dysfunction as shown in non-neuropathic 2years-old mice (Gaubert et al., 2007) and non-neuropathic older subjects (Fromy et al., 2010). This gradual endothelial dysfunction with ageing is largely reported in humans (Algotsson et al., 1995; Holowatz et al., 2005; Rossi et al., 2002; Taddei et al., 1995; Tao et al., 2004) and in animals (Muller-Delp et al., 2002; Woodman et al., 2003) due to lower levels/availabilities of nitric oxide (NO) and prostaglandins (PG) (Brandes et al., 2005; Holowatz and Kenney, 2009; Holowatz et al., 2010) or changes in the contribution of each endothelial factor including endothelium-derived hyperpolarizing factor (EDHF) (Gaubert et al., 2007; Matz and Andriantsitohaina, 2003). In addition, accentuation of glucose metabolism via the aldose reductase pathway leading to an increase to the quantity of advanced glycation endproducts (AGEs) contributes to age-related vascular dysfunction (Hallam et al., 2010). Considerable evidence has been published indicating that increased production of reactive oxygen species (ROS), mainly superoxide, also promotes endothelial dysfunction by generating damages at the level of cells such as DNA break and mutation, inactivation of proteins and enzymes, sugar oxidation and lipid peroxidation of the polyunsaturated fattyacids (Donato et al., 2007; Marin et al., 2013; Marin, 1995; van der Loo et al., 2000). In contrast, the relaxing capacity of the vascular smooth muscle to an exogeneous NO donor was preserved in the skin during the ageing process (Algotsson et al., 1995; Fromy et al., 2010; Gaubert et al., 2007; Muller-Delp et al., 2002; Rossi et al., 2002; Taddei et al., 1995; Tao et al., 2004; Woodman et al., 2003). In addition to this endothelial dysfunction with ageing, altered neurovascular interaction can be due to decreased activity of the axon reflex mechanism, since the synthesis, the storage and the secretion of neurotransmitters (such as CGRP, SP, ATP. . .) is decreased with increasing age (Helme and McKernan, 1986; Khalil et al., 1994; Ma et al., 2009). Marked reductions of

acetylcholinesterase (AChE) histochemical staining and of vasoactive intestinal polypeptide (VIP)- and CGRP-like immunoreactivity were observed in nerves around sweat glands of old rats (AbdelRahman and Cowen, 1994). In the sub-epidermis, PGP- and CGRP-like immunoreactive nerves were also significantly reduced in old rats (Abdel-Rahman and Cowen, 1994). These neurochemical changes in the peripheral nervous system could thus contribute to functional decrements, including tactile defect. Illustrated by the vasodilation in response to local pressure (PIV) highly sensitive to CGRP in humans, rats and mice (Fromy et al., 1998, 2000, 2012), the presence of sensory peripheral neuropathy worsened PIV alteration during ageing (Fromy et al., 2010). In the presence of tactile defect, individuals are totally deprived of a physiologically appropriate adjustment of local vasomotor function due to pressure detection failure putting the skin at high risk for pressure ulcers (Fromy et al., 2012). 5. Other relevant effects of ageing 5.1. Structural changes of the skin All the tissue layers that constitute the skin undergo dramatic changes with age (Bailey, 2001; Farage et al., 2007; Wu et al., 2011), including reduced epidermal thickness mainly due to a slower renewal rate of keratinocytes and reduced dermal thickness accompanied by a decrease in number of mast cells, fibroblasts and sebaceous glands, as well as flattened dermal–epidermal junction (Fig. 2, right panel). The generation of collagen, elastin and glycosaminoglycans (especially hyaluronic acid and dermatan sulphate) is also reduced in old dermis leading to loss of elasticity/stiffness associated with a decrease in the visco-elastic component (Varani et al., 2000, 2006; Zahouani et al., 2009), and major dehydration (Guergova and Dufour, 2011; Ramos et al., 2012; Varani et al., 2000). Although the cutaneous hydration did not affect vibrotactile detection thresholds, it did affect perception of textured surfaces (Verrillo et al., 1998). However, whether these age-related structural modifications could contribute to the defective tactile perception is unknown. 5.2. Higher brain structures Since the sensory stimuli are transmitted to higher brain structures (Roudaut et al., 2012), any modifications occurring in the central nervous system could also contribute to decrease the tactile sensitivity with ageing. Indeed the age-related degradation of tactile perception correlates with enhancement of cortical excitability (Lenz et al., 2012). The increases in peak and interpeak latencies attributable to increased conduction time in older subjects are observed in the median nerve, cervical spinal cord, brain-stem auditory pathways, and somatosensory and visual cortex (Allison et al., 1984). The changes in human sensory systems with ageing are not uniform, but depend on specific portions of these systems (Allison et al., 1984; Kuba et al., 2012). In addition, the central nervous system in the ageing population is still capable of plastic changes, and this cortical plasticity could be the mechanism that compensates for the degradations that are known to naturally occur with age (Zhang et al., 2011). 6. Experimental models for ageing Although the molecular aspects of tactile sensation are mainly discovered with Caenorhabditis elegans and Drosophila melanogaster, the ageing effect on the tactile perception are mainly performed in mammalians, including humans. Study of ageing in humans is difficult because often associated diseases,

J. Decorps et al. / Ageing Research Reviews 13 (2014) 90–99

treatments and it is complicated to discriminate the effects due to the ageing and the effects due to other parameters. Human diseases with premature ageing can also be studied, such as Werner’s syndrome with the development of cutaneous diseases (hyperkeratosis, tended skin, spots of old age, subcutaneous atrophy), Hutchinson-Gilford disease (progeria) with premature cutaneous ageing (lines and wrinkles) and alopecia, Trisomy of chromosome 21 and diabetes. However investigations in humans are restricted compared to exploratory approaches (like modifying a gene to measure its effects on ageing) in animal models such as rodents that would not be possible in humans. For these reasons, accelerated and longevity ageing animal models, as well as human disease models illustrating a premature ageing are extensively used to study the age-related changes. In addition, scientists can better isolate the variable they want to investigate because animal studies are conducted in tightly controlled environments. The animals typically have a very structured daily regimen with limited exposure to pollutants, stressors, or other elements that could otherwise affect lifespan and health span. 6.1. Non mammalian models Regarding the molecular aspects of the mechanotransduction, including the tactile sensation, genetic analyses in the nematode C. elegans and Drosophila provided a breakthrough in understanding eukaryotic mechanotransduction by identifying several candidate touch-transducing channels (DEG/ENaCs and TRP channels) (Arnadottir and Chalfie, 2010). About ageing, a recent review describes three major endocrine- and nutrient-sensing signalling pathways with influence on C. elegan lifespan, the insulin/insulinlike growth factor (IGF), target of rapamycin (TOR), and germline signalling pathways (Lapierre and Hansen, 2012). In C. elegans, life span extension by inhibiting insulin-like signalling as seen in daf-2 and age-1 mutants is dependent on a forkhead transcription factor daf-16 (Ogg et al., 1997). Other studies pointed out the role of SESN-1 (Yang et al., 2013), bifidobacteria via activation of skn1 (Komura et al., 2013) and anti-inflammatory protection against oxidative stress (Grompone et al., 2012). Sharing great genetic similarities with the man (Reiter et al., 2001), many scientists use the drosophila like model for ageing and certain human diseases, such as the Parkinson’s or Huntington’s disease. The overexpression of the mitochondrial heat shock protein (Hsp)22 extends lifespan in drosophila via cell-protection mechanisms against oxidative injuries, corroborating the pivotal role of mitochondria in the process of ageing (Morrow et al., 2004). A recent review describes the advances in the identification of key players modulating the relationship between molecular ageing networks and immune signal transduction pathways in the fruit fly D. melanogaster (Eleftherianos and Castillo, 2012). 6.2. Mouse models Many models of ageing in mice have been previously reviewed (Kuro-o, 2001), including mice with Werner syndrome presenting premature loss of proliferative capacity in fibroblasts, mice with Cockayne syndrome (CSA−/− and CSB−/− ) or ataxia telangiectasia (Atm−/− ) developing neurological defects, mice with overexpression of growth hormone showing reduced replicative potential of fibroblasts and astogliosis in the brain, telomerase-deficient mice (mTR−/− ) presenting alopecia, skin lesions and delayed wound healing and senescence-accelerated mice (SAM) displaying brain atrophy. In addition, different models of human premature ageing exist, such as the progeroid mice deficient in the zinc metalloproteinase Zmpste24 (Zmpste24−/− ) (Bergo et al., 2002; Pendas et al., 2002), the gene-targeted mice with a Hutchinson-Gilford progeria syndrome mutation (LmnaHG/+ ) and LmnaG609G/G609G mice. In

95

all these accelerated ageing models, the progeria phenotype can be corrected by treatments (Fong et al., 2004; Osorio et al., 2012; Varela et al., 2008; Yang et al., 2006). A role of vitamin D in mammalian ageing is well documented (Holick and Chen, 2008; Lanske and Razzaque, 2007). In humans, vitamin D3 insufficiency increases age-related diseases and mortality (Giovannucci, 2005). In addition, vitamin D receptor (VDR) gene variants were linked to changes in cognitive function and depressive symptoms in elderly subjects (Kuningas et al., 2009). Accordingly, VDR genetic ablation promotes premature ageing in mice (about 10.6 months) similarly to those described in mouse models of hypervitaminosis D (Razzaque and Lanske, 2006). These mutant mice that are smaller in size and in weight show wrinkled skin, enlarged sebaceous glands, formation of dermal cysts, thinner layer of the subcutaneous fat, thickening of the skin and develop alopecia (Keisala et al., 2009). Klotho, originally identified as a mutated gene in a mouse strain, accelerates age-dependent loss of function in multiple agesensitive traits (Kuro-o et al., 1997). The short-lived klotho mutant mouse (about 2-month lifespan) displays premature ageinglike disorders, including infertility, arteriosclerosis, lipodystrophy, osteoporosis, ectopic calcification in various soft tissues, uncoordinated movement, impairment in cognitive function, severe hyperphosphatemia and emphysema (Arking et al., 2002; Kuro-o, 2008; Kuro-o et al., 1997; Lanske and Razzaque, 2007; Nabeshima, 2008). The klotho protein may thus function through a circulating humoral factor that regulates the development of age-related disorders or natural ageing processes by inhibiting intracellular insulin and IGF1 signalling (Kurosu et al., 2005; Takahashi et al., 2000). In contrast, the klotho-overexpressing transgenic mice exhibit significant resistance to oxidative stress associated with moderate resistance to insulin/IGF-1, which may partly explain why these mice live longer (about 20–30%) than wild-type mice (Kurosu et al., 2005). In brief, the klotho gene is considered as one of the ageingsuppressor genes identified in mammals that extends lifespan when over-expressed and causes a premature-ageing syndrome when disrupted. About the skin, the klotho-deficient mice display atrophic skin with reduced thickness of the dermal and epidermal layers, reduced number of hair follicles and almost absence of subcutaneous fat (Kuro-o, 2009). Both klotho-overexpressing and -deficient mice are well-adapted and interesting models to study tactile defect in the ageing process. The insulin/IGF signalling pathway has a conserved role in regulating lifespan in C. elegans, Drosophila and mice (Bartke, 2011b). Longevity of mice can be increased by spontaneous or experimentally induced mutations that interfere with the biosynthesis or actions of growth hormone (GH), IGF-1 or insulin in the adipose tissue. Recent reviews explain the role of the GH/IGF-1 axis in lifespan (Bartke, 2011a; Berryman et al., 2008), as reported in Drosophila (Giannakou and Partridge, 2007). In the mouse model heterozygous for a mutation in the IGF-I receptor gene (IGF-1R+/− ) displaying a normal size (at least until weaning) and fertility (Holzenberger, 2004), the spectrum of pathologies associated with death was comparable to wild-type populations, but the onset of pathologies seemed retarded (Holzenberger, 2004). This could be partly explained by increase of their oxidative stress resistance (Holzenberger et al., 2003). However the tactile sensitivity could be affected by the epidermal thinning, since the epidermal deletion of IGF-1R in mice progressively decreased epidermal thickness without affecting differentiation or apoptosis (Liu et al., 1993; Stachelscheid et al., 2008). 6.3. Rat models The mainly used rat strains displaying increased lifespan are Fisher 344 (F344), Brown Norway (BN), Fisher 344 × Brown Norway

96

J. Decorps et al. / Ageing Research Reviews 13 (2014) 90–99

F1 (F344/BN) and Lou/c rats, presenting variability in ageing phenotype between them (Tanaka et al., 2002; Weindruch and Masoro, 1991). The F344 rat strain shows a shortest life expectancy (Lipman et al., 1996) and severe age-related pathology including endothelial dysfunction reported in arterioles from the soleus muscle with intact vascular smooth muscle capacity to relax (Muller-Delp et al., 2002). The BN strain is particularly amenable for autonomic and behavioural testing of aged animals because its weight gain over its lifetime with ad libitum access to food is limited compared to that of other strains, such as F344 and F344/BN rats (Turturro et al., 1999). In addition, the BN rats develop rarely age-related pathologies, such as glomerulonephritis, pneumonitis and pituitary and testicular tumours, unlike F344 or F344/BN rats (Gruenewald et al., 1992; Lipman et al., 1996). However in BN rats, it has been observed with ageing the presence of numerous ruptures in the internal elastic lamina in the abdominal segment (Capdeville et al., 1989), a generalized deficit in elastin content related to a defective synthesis of tropoelastin (Kota et al., 2007; Sauvage et al., 1999) and an increase of the carotid stiffness without significant change in blood arterial pressure (Maurice et al., 2012). In addition, cortical processing deficits were observed in the primary auditory cortex in 26–32-month-old BN rats (de Villers-Sidani et al., 2010). The Lou/c rats represent a model of healthy ageing with metabolic and neuroendocrine functions (Alliot et al., 2002; Perrin et al., 2003; Veyrat-Durebex et al., 2005), cognition and synaptic plasticity and memory capacity preserved with age (Kollen et al., 2010), at least up to 24 months. The Lou/c rat strain has an increased longevity (Veyrat-Durebex and Alliot, 1997) without developing age-related obesity due to a spontaneously reduced food intake (Couturier et al., 2002) and an impulsive locomotor activity until several kilometres per day (Servais et al., 2003). As a consequence, the Lou/c rats have a low body mass and a percentage of fat mass constant throughout their life (Boghossian et al., 2000). 7. Concluding remarks Ageing affects morphological and functional elements involved in tactile detection, encoding and/or transmission, as well as the skin itself. A combination of several changes would thus contribute to the effect of ageing on touch sensation leading to tactile defect with advancing age largely reported. To describe the ageing process and investigate the age-related pathologies, researchers can follow individuals throughout their lives (longitudinal studies) or compare young and old individuals (cross-sectional studies). In cross-sectional studies, differences between adult and old individuals have often been based on comparisons of only two experimental groups. Multiple time points should be favoured to take into account the life span, as previously pointed out (Coleman et al., 1990), since evaluation at multiple age points demonstrated that most of the age-related changes are not linear throughout life (Bouche et al., 1993; Ceballos et al., 1999; Verdu et al., 2000). Both types of studies are observational, not mechanistic, thus promoting the use of experimental models. Further studies are needed to better understand the underlying mechanisms leading to defective tactile function with increasing age and improve therapeutic interventions. References Abdel-Rahman, T.A., Cowen, T., 1994. Neurodegeneration in sweat glands and skin of aged rats. J. Auton. Nerv. Syst. 46, 55–63. Adinolfi, A.M., Yamuy, J., Morales, F.R., Chase, M.H., 1991. Segmental demyelination in peripheral nerves of old cats. Neurobiol. Aging 12, 175–179. Algotsson, A., Nordberg, A., Winblad, B., 1995. Influence of age and gender on skin vessel reactivity to endothelium-dependent and endothelium-independent vasodilators tested with iontophoresis and a laser Doppler perfusion imager. J. Gerontol. A. Biol. Sci. Med. Sci. 50, M121–M127.

Alliot, J., Boghossian, S., Jourdan, D., Veyrat-Durebex, C., Pickering, G., Meynial-Denis, D., Gaumet, N., 2002. The LOU/c/jall rat as an animal model of healthy aging? J. Gerontol. A. Biol. Sci. Med. Sci. 57, B312–B320. Allison, T., Hume, A.L., Wood, C.C., Goff, W.R., 1984. Developmental and aging changes in somatosensory, auditory and visual evoked potentials. Electroencephalogr. Clin. Neurophysiol. 58, 14–24. Arking, D.E., Krebsova, A., Macek Sr., M., Macek Jr., M., Arking, A., Mian, I.S., Fried, L., Hamosh, A., Dey, S., McIntosh, I., Dietz, H.C., 2002. Association of human aging with a functional variant of klotho. Proc. Natl. Acad. Sci. U. S. A. 99, 856–861. Arnadottir, J., Chalfie, M., 2010. Eukaryotic mechanosensitive channels. Annu. Rev. Biophys. 39, 111–137. Aydog, S.T., Korkusuz, P., Doral, M.N., Tetik, O., Demirel, H.A., 2006. Decrease in the numbers of mechanoreceptors in rabbit ACL: the effects of ageing. Knee Surg. Sports Traumatol. Arthrosc. 14, 325–329. Bailey, A.J., 2001. Molecular mechanisms of ageing in connective tissues. Mech. Ageing Dev. 122, 735–755. Bartke, A., 2011a. Pleiotropic effects of growth hormone signaling in aging. Trends Endocrinol. Metab. 22, 437–442. Bartke, A., 2011b. Single-gene mutations and healthy ageing in mammals. Philos. Trans. R. Soc. Lond. B: Biol. Sci. 366, 28–34. Baumann, K.I., Hamann, W., Leung, M.S., 1986. Mechanical properties of skin and responsiveness of slowly adapting type I mechanoreceptors in rats at different ages. J. Physiol. 371, 329–337. Bergo, M.O., Gavino, B., Ross, J., Schmidt, W.K., Hong, C., Kendall, L.V., Mohr, A., Meta, M., Genant, H., Jiang, Y., Wisner, E.R., Van Bruggen, N., Carano, R.A., Michaelis, S., Griffey, S.M., Young, S.G., 2002. Zmpste24 deficiency in mice causes spontaneous bone fractures, muscle weakness, and a prelamin A processing defect. Proc. Natl. Acad. Sci. U. S. A. 99, 13049–13054. Berryman, D.E., Christiansen, J.S., Johannsson, G., Thorner, M.O., Kopchick, J.J., 2008. Role of the GH/IGF-1 axis in lifespan and healthspan: lessons from animal models. Growth Horm. IGF Res. 18, 455–471. Besne, I., Descombes, C., Breton, L., 2002. Effect of age and anatomical site on density of sensory innervation in human epidermis. Arch. Dermatol. 138, 1445– 1450. Boghossian, S., Veyrat-Durebex, C., Alliot, J., 2000. Age-related changes in adaptive macronutrient intake in swimming male and female Lou rats. Physiol. Behav. 69, 231–238. Bolton, C.F., Winkelmann, R.K., Dyck, P.J., 1966. A quantitative study of Meissner’s corpuscles in man. Neurology 16, 1–9. Bouche, P., Cattelin, F., Saint-Jean, O., Leger, J.M., Queslati, S., Guez, D., Moulonguet, A., Brault, Y., Aquino, J.P., Simunek, P., 1993. Clinical and electrophysiological study of the peripheral nervous system in the elderly. J. Neurol. 240, 263–268. Brandes, R.P., Fleming, I., Busse, R., 2005. Endothelial aging. Cardiovasc. Res. 66, 286–294. Campero, M., Serra, J., Ochoa, J.L., 1996. C-polymodal nociceptors activated by noxious low temperature in human skin. J. Physiol. 497, 565–572. Capdeville, M., Coutard, M., Osborne-Pellegrin, M.J., 1989. Spontaneous rupture of the internal elastic lamina in the rat: the manifestation of a genetically determined factor which may be linked to vascular fragility. Blood Vessels 26, 197–212. Cauna, N., Mannan, G., 1958. The structure of human digital pacinian corpuscles (corpus cula lamellosa) and its functional significance. J. Anat. 92, 1–20. Ceballos, D., Cuadras, J., Verdu, E., Navarro, X., 1999. Morphometric and ultrastructural changes with ageing in mouse peripheral nerve. J. Anat. 195 (Pt 4), 563–576. Cerimele, D., Celleno, L., Serri, F., 1990. Physiological changes in ageing skin. Br. J. Dermatol. 122 (Suppl. 35), 13–20. Chalfie, M., 2009. Neurosensory mechanotransduction. Nat. Rev. Mol. Cell Biol. 10, 44–52. Chang, Y.C., Lin, W.M., Hsieh, S.T., 2004. Effects of aging on human skin innervation. Neuroreport 15, 149–153. Chase, M.H., Engelhardt, J.K., Adinolfi, A.M., Chirwa, S.S., 1992. Age-dependent changes in cat masseter nerve: an electrophysiological and morphological study. Brain Res. 586, 279–288. Cole, J., Bushnell, M.C., McGlone, F., Elam, M., Lamarre, Y., Vallbo, A., Olausson, H., 2006. Unmyelinated tactile afferents underpin detection of low-force monofilaments. Muscle Nerve 34, 105–107. Coleman, P., Finch, C., Joseph, J., 1990. The need for multiple time points in aging studies. Neurobiol. Aging 11, 1–2. Coste, B., Xiao, B., Santos, J.S., Syeda, R., Grandl, J., Spencer, K.S., Kim, S.E., Schmidt, M., Mathur, J., Dubin, A.E., Montal, M., Patapoutian, A., 2012. Piezo proteins are poreforming subunits of mechanically activated channels. Nature 483, 176–181. Couturier, K., Servais, S., Koubi, H., Sempore, B., Sornay-Mayet, M.H., Cottet-Emard, J.M., Lavoie, J.M., Favier, R., 2002. Metabolic characteristics and body composition in a model of anti-obese rats (Lou/C). Obes. Res. 10, 188–195. Dalsgaard, C.J., Rydh, M., Haegerstrand, A., 1989. Cutaneous innervation in man visualized with protein gene product 9.5 (PGP 9.5) antibodies. Histochemistry 92, 385–390. De Backer, D., Ospina-Tascon, G., Salgado, D., Favory, R., Creteur, J., Vincent, J.L., 2010. Monitoring the microcirculation in the critically ill patient: current methods and future approaches. Intensive Care Med. 36, 1813–1825. de Villers-Sidani, E., Alzghoul, L., Zhou, X., Simpson, K.L., Lin, R.C., Merzenich, M.M., 2010. Recovery of functional and structural age-related changes in the rat primary auditory cortex with operant training. Proc. Natl. Acad. Sci. U. S. A. 107, 13900–13905. Demiot, C., Tartas, M., Fromy, B., Abraham, P., Saumet, J.L., Sigaudo-Roussel, D., 2006. Aldose reductase pathway inhibition improved vascular and C-fiber functions,

J. Decorps et al. / Ageing Research Reviews 13 (2014) 90–99 allowing for pressure-induced vasodilation restoration during severe diabetic neuropathy. Diabetes 55, 1478–1483. Di Iorio, A., Cherubini, A., Volpato, S., Sparvieri, E., Lauretani, F., Franceschi, C., Senin, U., Abate, G., Paganelli, R., Martin, A., Andres-Lacueva, C., Ferrucci, L., 2006. Markers of inflammation, vitamin E and peripheral nervous system function the InCHIANTI study. Neurobiol. Aging 27, 1280–1288. Donato, A.J., Eskurza, I., Silver, A.E., Levy, A.S., Pierce, G.L., Gates, P.E., Seals, D.R., 2007. Direct evidence of endothelial oxidative stress with aging in humans: relation to impaired endothelium-dependent dilation and upregulation of nuclear factorkappaB. Circ. Res. 100, 1659–1666. Eleftherianos, I., Castillo, J.C., 2012. Molecular mechanisms of aging and immune system regulation in Drosophila. Int. J. Mol. Sci. 13, 9826–9844. Farage, M.A., Miller, K.W., Elsner, P., Maibach, H.I., 2007. Structural characteristics of the aging skin: a review. Cutan. Ocul. Toxicol. 26, 343–357. Farage, M.A., Miller, K.W., Elsner, P., Maibach, H.I., 2008. Functional and physiological characteristics of the aging skin. Aging Clin. Exp. Res. 20, 195–200. Fenske, N.A., Lober, C.W., 1986. Structural and functional changes of normal aging skin. J. Am. Acad. Dermatol. 15, 571–585. Fizanne, L., Sigaudo-Roussel, D., Saumet, J.L., Fromy, B., 2004. Evidence for the involvement of VPAC1 and VPAC2 receptors in pressure-induced vasodilatation in rodents. J. Physiol. 554, 519–528. Fong, L.G., Ng, J.K., Meta, M., Cote, N., Yang, S.H., Stewart, C.L., Sullivan, T., Burghardt, A., Majumdar, S., Reue, K., Bergo, M.O., Young, S.G., 2004. Heterozygosity for Lmna deficiency eliminates the progeria-like phenotypes in Zmpste24-deficient mice. Proc. Natl. Acad. Sci. U. S. A. 101, 18111–18116. Fromy, B., Abraham, P., Saumet, J.L., 1998. Non-nociceptive capsaicin-sensitive nerve terminal stimulation allows for an original vasodilatory reflex in the human skin. Brain Res. 811, 166–168. Fromy, B., Lingueglia, E., Sigaudo-Roussel, D., Saumet, J.L., Lazdunski, M., 2012. Asic3 is a neuronal mechanosensor for pressure-induced vasodilation that protects against pressure ulcers. Nat. Med. 18, 1205–1207. Fromy, B., Merzeau, S., Abraham, P., Saumet, J.L., 2000. Mechanisms of the cutaneous vasodilator response to local external pressure application in rats: involvement of CGRP, neurokinins, prostaglandins and NO. Br. J. Pharmacol. 131, 1161– 1171. Fromy, B., Sigaudo-Roussel, D., Gaubert-Dahan, M.L., Rousseau, P., Abraham, P., Benzoni, D., Berrut, G., Saumet, J.L., 2010. Aging-associated sensory neuropathy alters pressure-induced vasodilation in humans. J. Invest. Dermatol. 130, 849–855. Fromy, B., Sigaudo-Roussel, D., Saumet, J.L., 2008. Cutaneous neurovascular interaction involved in tactile sensation. Cardiovasc. Hematol. Agents Med. Chem. 6, 337–342. Fundin, B.T., Bergman, E., Ulfhake, B., 1997. Alterations in mystacial pad innervation in the aged rat. Exp. Brain Res. 117, 324–340. Garry, A., Fromy, B., Blondeau, N., Henrion, D., Brau, F., Gounon, P., Guy, N., Heurteaux, C., Lazdunski, M., Saumet, J.L., 2007. Altered acetylcholine, bradykinin and cutaneous pressure-induced vasodilation in mice lacking the TREK1 potassium channel: the endothelial link. EMBO Rep. 8, 354–359. Gaubert, M.L., Sigaudo-Roussel, D., Tartas, M., Berrut, G., Saumet, J.L., Fromy, B., 2007. Endothelium-derived hyperpolarizing factor as an in vivo back-up mechanism in the cutaneous microcirculation in old mice. J. Physiol. 585, 617–626. Gescheider, G.A., Bolanowski, S.J., Hall, K.L., Hoffman, K.E., Verrillo, R.T., 1994. The effects of aging on information-processing channels in the sense of touch: I. Absolute sensitivity. Somatosens. Mot. Res. 11, 345–357. Giannakou, M.E., Partridge, L., 2007. Role of insulin-like signalling in Drosophila lifespan. Trends Biochem. Sci. 32, 180–188. Gibbons, C.H., Griffin, J.W., Polydefkis, M., Bonyhay, I., Brown, A., Hauer, P.E., McArthur, J.C., 2006. The utility of skin biopsy for prediction of progression in suspected small fiber neuropathy. Neurology 66, 256–258. Giovannucci, E., 2005. The epidemiology of vitamin D and cancer incidence and mortality: a review (United States). Cancer Causes Control 16, 83–95. Goransson, L.G., Mellgren, S.I., Lindal, S., Omdal, R., 2004. The effect of age and gender on epidermal nerve fiber density. Neurology 62, 774–777. Grompone, G., Martorell, P., Llopis, S., Gonzalez, N., Genoves, S., Mulet, A.P., Fernandez-Calero, T., Tiscornia, I., Bollati-Fogolin, M., Chambaud, I., Foligne, B., Montserrat, A., Ramon, D., 2012. Anti-inflammatory Lactobacillus rhamnosus CNCM I-3690 strain protects against oxidative stress and increases lifespan in Caenorhabditis elegans. PLoS One 7, e52493. Gruenewald, D.A., Hess, D.L., Wilkinson, C.W., Matsumoto, A.M., 1992. Excessive testicular progesterone secretion in aged male Fischer 344 rats: a potential cause of age-related gonadotropin suppression and confounding variable in aging studies. J. Gerontol. 47, B164–B170. Guergova, S., Dufour, A., 2011. Thermal sensitivity in the elderly: a review. Ageing Res. Rev. 10, 80–92. Hallam, K.M., Li, Q., Ananthakrishnan, R., Kalea, A., Zou, Y.S., Vedantham, S., Schmidt, A.M., Yan, S.F., Ramasamy, R., 2010. Aldose reductase and AGE-RAGE pathways: central roles in the pathogenesis of vascular dysfunction in aging rats. Aging Cell 9, 776–784. Helme, R.D., McKernan, S., 1986. Effects of age on the axon reflex response to noxious chemical stimulation. Clin. Exp. Neurol. 22, 57–61. Herrmann, D.N., Griffin, J.W., Hauer, P., Cornblath, D.R., McArthur, J.C., 1999. Epidermal nerve fiber density and sural nerve morphometry in peripheral neuropathies. Neurology 53, 1634–1640. Holick, M.F., Chen, T.C., 2008. Vitamin D deficiency: a worldwide problem with health consequences. Am. J. Clin. Nutr. 87, 1080S–1086S.

97

Holland, N.R., Stocks, A., Hauer, P., Cornblath, D.R., Griffin, J.W., McArthur, J.C., 1997. Intraepidermal nerve fiber density in patients with painful sensory neuropathy. Neurology 48, 708–711. Holowatz, L.A., Kenney, W.L., 2009. Chronic low-dose aspirin therapy attenuates reflex cutaneous vasodilation in middle-aged humans. J. Appl. Physiol. 106, 500–505. Holowatz, L.A., Thompson-Torgerson, C., Kenney, W.L., 2010. Aging and the control of human skin blood flow. Front. Biosci. 15, 718–739. Holowatz, L.A., Thompson, C.S., Minson, C.T., Kenney, W.L., 2005. Mechanisms of acetylcholine-mediated vasodilatation in young and aged human skin. J. Physiol. 563, 965–973. Holzenberger, M., 2004. The GH/IGF-I axis and longevity. Eur. J. Endocrinol. 151 (Suppl. 1), S23L 27. Holzenberger, M., Dupont, J., Ducos, B., Leneuve, P., Geloen, A., Even, P.C., Cervera, P., Le Bouc, Y., 2003. IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice. Nature 421, 182–187. Jacobs, J.M., Love, S., 1985. Qualitative and quantitative morphology of human sural nerve at different ages. Brain 108 (Pt 4), 897–924. Johnson, K.O., 2001. The roles and functions of cutaneous mechanoreceptors. Curr. Opin. Neurobiol. 11, 455–461. Kalisch, T., Ragert, P., Schwenkreis, P., Dinse, H.R., Tegenthoff, M., 2009. Impaired tactile acuity in old age is accompanied by enlarged hand representations in somatosensory cortex. Cereb. Cortex 19, 1530–1538. Kanda, T., Tsukagoshi, H., Oda, M., Miyamoto, K., Tanabe, H., 1991. Morphological changes in unmyelinated nerve fibres in the sural nerve with age. Brain 114, 585–599. Keisala, T., Minasyan, A., Lou, Y.R., Zou, J., Kalueff, A.V., Pyykko, I., Tuohimaa, P., 2009. Premature aging in vitamin D receptor mutant mice. J. Steroid Biochem. Mol. Biol. 115, 91–97. Kennedy, W.R., Nolano, M., Wendelschafer-Crabb, G., Johnson, T.L., Tamura, E., 1999. A skin blister method to study epidermal nerves in peripheral nerve disease. Muscle Nerve 22, 360–371. Kennedy, W.R., Selim, M.M., Brink, T.S., Hodges, J.S., Wendelschafer-Crabb, G., Foster, S.X., Nolano, M., Provitera, V., Simone, D.A., 2011. A new device to quantify tactile sensation in neuropathy. Neurology 76, 1642–1649. Kenney, W.L., Morgan, A.L., Farquhar, W.B., Brooks, E.M., Pierzga, J.M., Derr, J.A., 1997. Decreased active vasodilator sensitivity in aged skin. Am. J. Physiol. 272, H1609–H1614. Khalil, Z., Ralevic, V., Bassirat, M., Dusting, G.J., Helme, R.D., 1994. Effects of ageing on sensory nerve function in rat skin. Brain Res. 641, 265–272. Kihara, M., Nickander, K.K., Low, P.A., 1991. The effect of aging on endoneurial blood flow, hyperemic response and oxygen-free radicals in rat sciatic nerve. Brain Res. 562, 1–5. Kim, S.E., Coste, B., Chadha, A., Cook, B., Patapoutian, A., 2012. The role of Drosophila Piezo in mechanical nociception. Nature 483, 209–212. Kollen, M., Stephan, A., Faivre-Bauman, A., Loudes, C., Sinet, P.M., Alliot, J., Billard, J.M., Epelbaum, J., Dutar, P., Jouvenceau, A., 2010. Preserved memory capacities in aged Lou/C/Jall rats. Neurobiol. Aging 31, 129–142. Komura, T., Ikeda, T., Yasui, C., Saeki, S., Nishikawa, Y., 2013. Mechanism underlying prolongevity induced by bifidobacteria in Caenorhabditis elegans. Biogerontology 14, 73–87. Kota, L., Osborne-Pellegrin, M., Schulz, H., Behmoaras, J., Coutard, M., Gong, M., Hubner, N., 2007. Quantitative genetic basis of arterial phenotypes in the Brown Norway rat. Physiol. Genomics 30, 17–25. Kuba, M., Kremlacek, J., Langrova, J., Kubova, Z., Szanyi, J., Vit, F., 2012. Aging effect in pattern, motion and cognitive visual evoked potentials. Vision Res. 62, 9–16. Kuningas, M., Mooijaart, S.P., Jolles, J., Slagboom, P.E., Westendorp, R.G., van Heemst, D., 2009. VDR gene variants associate with cognitive function and depressive symptoms in old age. Neurobiol. Aging 30, 466–473. Kuro-o, M., 2001. Disease model: human aging. Trends Mol. Med. 7, 179–181. Kuro-o, M., 2008. Klotho as a regulator of oxidative stress and senescence. Biol. Chem. 389, 233–241. Kuro-o, M., 2009. Klotho and aging. Biochim. Biophys. Acta 1790, 1049–1058. Kuro-o, M., Matsumura, Y., Aizawa, H., Kawaguchi, H., Suga, T., Utsugi, T., Ohyama, Y., Kurabayashi, M., Kaname, T., Kume, E., Iwasaki, H., Iida, A., Shiraki-Iida, T., Nishikawa, S., Nagai, R., Nabeshima, Y.I., 1997. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature 390, 45–51. Kurosu, H., Yamamoto, M., Clark, J.D., Pastor, J.V., Nandi, A., Gurnani, P., McGuinness, O.P., Chikuda, H., Yamaguchi, M., Kawaguchi, H., Shimomura, I., Takayama, Y., Herz, J., Kahn, C.R., Rosenblatt, K.P., Kuro-o, M., 2005. Suppression of aging in mice by the hormone Klotho. Science 309, 1829–1833. LaMotte, R.H., Whitehouse, J., 1986. Tactile detection of a dot on a smooth surface: peripheral neural events. J. Neurophysiol. 56, 1109–1128. Lanske, B., Razzaque, M.S., 2007. Premature aging in klotho mutant mice: cause or consequence? Ageing Res. Rev. 6, 73–79. Lapierre, L.R., Hansen, M., 2012. Lessons from C. elegans: signaling pathways for longevity. Trends Endocrinol. Metab. 23, 637–644. Lauria, G., Holland, N., Hauer, P., Cornblath, D.R., Griffin, J.W., McArthur, J.C., 1999. Epidermal innervation: changes with aging, topographic location, and in sensory neuropathy. J. Neurol. Sci. 164, 172–178. Lauria, G., Bakkers, M., Schmitz, C., Lombardi, R., Penza, P., Devigili, G., Smith, A.G., Hsieh, S.T., Mellgren, S.I., Umapathi, T., Ziegler, D., Faber, C.G., Merkies, I.S., 2010. Intraepidermal nerve fiber density at the distal leg: a worldwide normative reference study. J. Peripher. Nerv. Syst. 15, 202–207. Lenz, M., Tegenthoff, M., Kohlhaas, K., Stude, P., Hoffken, O., Gatica Tossi, M.A., Kalisch, T., Dinse, H.R., 2012. Increased excitability of somatosensory cortex

98

J. Decorps et al. / Ageing Research Reviews 13 (2014) 90–99

in aged humans is associated with impaired tactile acuity. J. Neurosci. 32, 1811–1816. Leveque, J.L., Dresler, J., Ribot-Ciscar, E., Roll, J.P., Poelman, C., 2000. Changes in tactile spatial discrimination and cutaneous coding properties by skin hydration in the elderly. J. Invest. Dermatol. 115, 454–458. Lin, Y.H., Hsieh, S.C., Chao, C.C., Chang, Y.C., Hsieh, S.T., 2005. Influence of aging on thermal and vibratory thresholds of quantitative sensory testing. J. Peripher. Nerv. Syst. 10, 269–281. Lipman, R.D., Chrisp, C.E., Hazzard, D.G., Bronson, R.T., 1996. Pathologic characterization of brown Norway, brown Norway × Fischer 344, and Fischer 344 × brown Norway rats with relation to age. J. Gerontol. A. Biol. Sci. Med. Sci. 51, B54–B59. Liu, J.P., Baker, J., Perkins, A.S., Robertson, E.J., Efstratiadis, A., 1993. Mice carrying null mutations of the genes encoding insulin-like growth factor I (Igf-1) and type 1 IGF receptor (Igf1r). Cell 75, 59–72. Lumpkin, E.A., Marshall, K.L., Nelson, A.M., 2010. The cell biology of touch. J. Cell Biol. 191, 237–248. Ma, Y.S., Wu, S.B., Lee, W.Y., Cheng, J.S., Wei, Y.H., 2009. Response to the increase of oxidative stress and mutation of mitochondrial DNA in aging. Biochim. Biophys. Acta 1790, 1021–1029. Marin, C., Yubero-Serrano, E.M., Lopez-Miranda, J., Perez-Jimenez, F., 2013. Endothelial aging associated with oxidative stress can be modulated by a healthy mediterranean diet. Int. J. Mol. Sci. 14, 8869–8889. Marin, J., 1995. Age-related changes in vascular responses: a review. Mech. Ageing Dev. 79, 71–114. Mathewson, R.C., Nava, P.B., 1985. Effects of age on Meissner corpuscles: a study of silver-impregnated neurites in mouse digital pads. J. Comp. Neurol. 231, 250–259. Matz, R.L., Andriantsitohaina, R., 2003. Age-related endothelial dysfunction: potential implications for pharmacotherapy. Drugs Aging 20, 527–550. Maurice, R.L., Dahdah, N., Tremblay, J., 2012. Imaging-based biomarkers: characterization of post-kawasaki vasculitis in infants and hypertension phenotype in rat model. Int. J. Vasc. Med. 2012, 364145. McCarthy, B.G., Hsieh, S.T., Stocks, A., Hauer, P., Macko, C., Cornblath, D.R., Griffin, J.W., McArthur, J.C., 1995. Cutaneous innervation in sensory neuropathies: evaluation by skin biopsy. Neurology 45, 1848–1855. McGlone, F., Reilly, D., 2010. The cutaneous sensory system. Neurosci. Biobehav. Rev. 34, 148–159. Melcangi, R.C., Magnaghi, V., Cavarretta, I., Martini, L., Piva, F., 1998. Age-induced decrease of glycoprotein Po and myelin basic protein gene expression in the rat sciatic nerve. Repair by steroid derivatives. Neuroscience 85, 569–578. Melcangi, R.C., Magnaghi, V., Martini, L., 2000. Aging in peripheral nerves: regulation of myelin protein genes by steroid hormones. Prog. Neurobiol. 60, 291–308. Minson, C.T., Holowatz, L.A., Wong, B.J., Kenney, W.L., Wilkins, B.W., 2002. Decreased nitric oxide- and axon reflex-mediated cutaneous vasodilation with age during local heating. J. Appl. Physiol. 93, 1644–1649. Misery, L., 1997. Skin, immunity and the nervous system. Br. J. Dermatol. 137, 843–850. Morisawa, Y., 1998. Morphological study of mechanoreceptors on the coracoacromial ligament. J. Orthop. Sci. 3, 102–110. Morrow, G., Samson, M., Michaud, S., Tanguay, R.M., 2004. Overexpression of the small mitochondrial Hsp22 extends Drosophila life span and increases resistance to oxidative stress. FASEB J. 18, 598–599. Muller-Delp, J.M., Spier, S.A., Ramsey, M.W., Delp, M.D., 2002. Aging impairs endothelium-dependent vasodilation in rat skeletal muscle arterioles. Am. J. Physiol. Heart Circ. Physiol. 283, H1662–H1672. Munce, T.A., Kenney, W.L., 2003. Age-specific modification of local cutaneous vasodilation by capsaicin-sensitive primary afferents. J. Appl. Physiol. 95, 1016–1024. Nabeshima, Y., 2008. The discovery of alpha-Klotho and FGF23 unveiled new insight into calcium and phosphate homeostasis. Cell. Mol. Life Sci. 65, 3218–3230. Namer, B., Barta, B., Orstavik, K., Schmidt, R., Carr, R., Schmelz, M., Handwerker, H.O., 2009. Microneurographic assessment of C-fibre function in aged healthy subjects. J. Physiol. 587, 419–428. Nilius, B., Honore, E., 2012. Sensing pressure with ion channels. Trends Neurosci. 35, 477–486. Ogg, S., Paradis, S., Gottlieb, S., Patterson, G.I., Lee, L., Tissenbaum, H.A., Ruvkun, G., 1997. The Fork head transcription factor DAF-16 transduces insulin-like metabolic and longevity signals in C. elegans. Nature 389, 994–999. Olausson, H., Wessberg, J., Morrison, I., McGlone, F., Vallbo, A., 2010. The neurophysiology of unmyelinated tactile afferents. Neurosci. Biobehav. Rev. 34, 185–191. Orstavik, K., Namer, B., Schmidt, R., Schmelz, M., Hilliges, M., Weidner, C., Carr, R.W., Handwerker, H., Jorum, E., Torebjork, H.E., 2006. Abnormal function of C-fibers in patients with diabetic neuropathy. J. Neurosci. 26, 11287–11294. Osorio, F.G., Barcena, C., Soria-Valles, C., Ramsay, A.J., de Carlos, F., Cobo, J., Fueyo, A., Freije, J.M., Lopez-Otin, C., 2012. Nuclear lamina defects cause ATM-dependent NF-kappaB activation and link accelerated aging to a systemic inflammatory response. Genes Dev. 26, 2311–2324. Panoutsopoulou, I.G., Wendelschafer-Crabb, G., Hodges, J.S., Kennedy, W.R., 2009. Skin blister and skin biopsy to quantify epidermal nerves: a comparative study. Neurology 72, 1205–1210. Pare, M., Albrecht, P.J., Noto, C.J., Bodkin, N.L., Pittenger, G.L., Schreyer, D.J., Tigno, X.T., Hansen, B.C., Rice, F.L., 2007. Differential hypertrophy and atrophy among all types of cutaneous innervation in the glabrous skin of the monkey hand during aging and naturally occurring type 2 diabetes. J. Comp. Neurol. 501, 543–567. Parkhouse, N., Le Quesne, P.M., 1988. Impaired neurogenic vascular response in patients with diabetes and neuropathic foot lesions. N. Engl. J. Med. 318, 1306–1309.

Pendas, A.M., Zhou, Z., Cadinanos, J., Freije, J.M., Wang, J., Hultenby, K., Astudillo, A., Wernerson, A., Rodriguez, F., Tryggvason, K., Lopez-Otin, C., 2002. Defective prelamin A processing and muscular and adipocyte alterations in Zmpste24 metalloproteinase-deficient mice. Nat. Genet. 31, 94–99. Periquet, M.I., Novak, V., Collins, M.P., Nagaraja, H.N., Erdem, S., Nash, S.M., Freimer, M.L., Sahenk, Z., Kissel, J.T., Mendell, J.R., 1999. Painful sensory neuropathy: prospective evaluation using skin biopsy. Neurology 53, 1641–1647. Perrin, D., Soulage, C., Pequignot, J.M., Geloen, A., 2003. Resistance to obesity in Lou/C rats prevents ageing-associated metabolic alterations. Diabetologia 46, 1489–1496. Perry, S.D., 2006. Evaluation of age-related plantar-surface insensitivity and onset age of advanced insensitivity in older adults using vibratory and touch sensation tests. Neurosci. Lett. 392, 62–67. Peters, A., 2002. The effects of normal aging on myelin and nerve fibers: a review. J. Neurocytol. 31, 581–593. Ramos, E.S.M., Boza, J.C., Cestari, T.F., 2012. Effects of age (neonates and elderly) on skin barrier function. Clin. Dermatol. 30, 274–276. Razzaque, M.S., Lanske, B., 2006. Hypervitaminosis D and premature aging: lessons learned from Fgf23 and Klotho mutant mice. Trends Mol. Med. 12, 298–305. Reinke, H., Dinse, H.R., 1996. Functional characterization of cutaneous mechanoreceptor properties in aged rats. Neurosci. Lett. 216, 171–174. Reiter, L.T., Potocki, L., Chien, S., Gribskov, M., Bier, E., 2001. A systematic analysis of human disease-associated gene sequences in Drosophila melanogaster. Genome Res. 11, 1114–1125. Rolke, R., Baron, R., Maier, C., Tolle, T.R., Treede, R.D., Beyer, A., Binder, A., Birbaumer, N., Birklein, F., Botefur, I.C., Braune, S., Flor, H., Huge, V., Klug, R., Landwehrmeyer, G.B., Magerl, W., Maihofner, C., Rolko, C., Schaub, C., Scherens, A., Sprenger, T., Valet, M., Wasserka, B., 2006. Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): standardized protocol and reference values. Pain 123, 231–243. Rossi, M., Cupisti, A., Mariani, S., Santoro, G., Pentimone, F., 2002. Endotheliumdependent and endothelium-independent skin vasoreactivity in the elderly. Aging Clin. Exp. Res. 14, 343–346. Roudaut, Y., Lonigro, A., Coste, B., Hao, J., Delmas, P., Crest, M., 2012. Touch sense: functional organization and molecular determinants of mechanosensitive receptors. Channels (Austin) 6, 234–245. Roustit, M., Cracowski, J.L., 2012. Non-invasive assessment of skin microvascular function in humans: an insight into methods. Microcirculation 19, 47–64. Rowe, J.W., Kahn, R.L., 1987. Human aging: usual and successful. Science 237, 143–149. Sauvage, M., Osborne-Pellegrin, M., Deslandes-Le Flohic, F., Jacob, M.P., 1999. Influence of elastin gene polymorphism on the elastin content of the aorta: a study in 2 strains of rat. Arterioscler. Thromb. Vasc. Biol. 19, 2308–2315. Selim, M.M., Wendelschafer-Crabb, G., Hodges, J.S., Simone, D.A., Foster, S.X., Vanhove, G.F., Kennedy, W.R., 2010. Variation in quantitative sensory testing and epidermal nerve fiber density in repeated measurements. Pain 151, 575– 581. Servais, S., Couturier, K., Koubi, H., Rouanet, J.L., Desplanches, D., Sornay-Mayet, M.H., Sempore, B., Lavoie, J.M., Favier, R., 2003. Effect of voluntary exercise on H2O2 release by subsarcolemmal and intermyofibrillar mitochondria. Free Radic. Biol. Med. 35, 24–32. Sherwood, T.W., Frey, E.N., Askwith, C.C., 2012. Structure and activity of the acidsensing ion channels. Am. J. Physiol. Cell Physiol. 303, C699–C710. Sigaudo-Roussel, D., Demiot, C., Fromy, B., Koitka, A., Leftheriotis, G., Abraham, P., Saumet, J.L., 2004. Early endothelial dysfunction severely impairs skin blood flow response to local pressure application in streptozotocin-induced diabetic mice. Diabetes 53, 1564–1569. Sommer, C., Lauria, G., 2007. Skin biopsy in the management of peripheral neuropathy. Lancet Neurol. 6, 632–642. Stachelscheid, H., Ibrahim, H., Koch, L., Schmitz, A., Tscharntke, M., Wunderlich, F.T., Scott, J., Michels, C., Wickenhauser, C., Haase, I., Bruning, J.C., Niessen, C.M., 2008. Epidermal insulin/IGF-1 signalling control interfollicular morphogenesis and proliferative potential through Rac activation. EMBO J. 27, 2091–2101. Stevens, J.C., Patterson, M.Q., 1995. Dimensions of spatial acuity in the touch sense: changes over the life span. Somatosens. Mot. Res. 12, 29–47. Taddei, S., Virdis, A., Mattei, P., Ghiadoni, L., Gennari, A., Fasolo, C.B., Sudano, I., Salvetti, A., 1995. Aging and endothelial function in normotensive subjects and patients with essential hypertension. Circulation 91, 1981–1987. Taguchi, T., Ota, H., Matsuda, T., Murase, S., Mizumura, K., 2010. Cutaneous C-fiber nociceptor responses and nociceptive behaviors in aged Sprague-Dawley rats. Pain 151, 771–782. Takahashi, Y., Kuro, O.M., Ishikawa, F., 2000. Aging mechanisms. Proc. Natl. Acad. Sci. U. S. A. 97, 12407–12408. Tanaka, S., Shito, A., Tamaya, N., Miyaishi, O., Nishimura, M., Ohno, T., 2002. Difference in average survival between F344/Du and F344/N rats is not due to genetic contamination. Arch. Gerontol. Geriatr. 34, 19–28. Tao, J., Jin, Y.F., Yang, Z., Wang, L.C., Gao, X.R., Lui, L., Ma, H., 2004. Reduced arterial elasticity is associated with endothelial dysfunction in persons of advancing age: comparative study of noninvasive pulse wave analysis and laser Doppler blood flow measurement. Am. J. Hypertens. 17, 654–659. Tew, G.A., Saxton, J.M., Klonizakis, M., Moss, J., Ruddock, A.D., Hodges, G.J., 2011. Aging and aerobic fitness affect the contribution of noradrenergic sympathetic nerves to the rapid cutaneous vasodilator response to local heating. J. Appl. Physiol. 110, 1264–1270. Thornbury, J.M., Mistretta, C.M., 1981. Tactile sensitivity as a function of age. J. Gerontol. 36, 34–39.

J. Decorps et al. / Ageing Research Reviews 13 (2014) 90–99 Thurstan, S.A., Gibbs, N.K., Langton, A.K., Griffiths, C.E., Watson, R.E., Sherratt, M.J., 2012. Chemical consequences of cutaneous photoageing. Chem. Cent. J. 6, 34. Turturro, A., Witt, W.W., Lewis, S., Hass, B.S., Lipman, R.D., Hart, R.W., 1999. Growth curves and survival characteristics of the animals used in the Biomarkers of Aging Program. J. Gerontol. A. Biol. Sci. Med. Sci. 54, B492–B501. Vallbo, A., Olausson, H., Wessberg, J., Norrsell, U., 1993. A system of unmyelinated afferents for innocuous mechanoreception in the human skin. Brain Res. 628, 301–304. Vallbo, A.B., Olausson, H., Wessberg, J., 1999. Unmyelinated afferents constitute a second system coding tactile stimuli of the human hairy skin. J. Neurophysiol. 81, 2753–2763. van der Loo, B., Labugger, R., Skepper, J.N., Bachschmid, M., Kilo, J., Powell, J.M., Palacios-Callender, M., Erusalimsky, J.D., Quaschning, T., Malinski, T., Gygi, D., Ullrich, V., Luscher, T.F., 2000. Enhanced peroxynitrite formation is associated with vascular aging. J. Exp. Med. 192, 1731–1744. Varani, J., Dame, M.K., Rittie, L., Fligiel, S.E., Kang, S., Fisher, G.J., Voorhees, J.J., 2006. Decreased collagen production in chronologically aged skin: roles of age-dependent alteration in fibroblast function and defective mechanical stimulation. Am. J. Pathol. 168, 1861–1868. Varani, J., Warner, R.L., Gharaee-Kermani, M., Phan, S.H., Kang, S., Chung, J.H., Wang, Z.Q., Datta, S.C., Fisher, G.J., Voorhees, J.J., 2000. Vitamin A antagonizes decreased cell growth and elevated collagen-degrading matrix metalloproteinases and stimulates collagen accumulation in naturally aged human skin. J. Invest. Dermatol. 114, 480–486. Varela, I., Pereira, S., Ugalde, A.P., Navarro, C.L., Suarez, M.F., Cau, P., Cadinanos, J., Osorio, F.G., Foray, N., Cobo, J., de Carlos, F., Levy, N., Freije, J.M., Lopez-Otin, C., 2008. Combined treatment with statins and aminobisphosphonates extends longevity in a mouse model of human premature aging. Nat. Med. 14, 767–772. Vega, J.A., Garcia-Suarez, O., Montano, J.A., Pardo, B., Cobo, J.M., 2009. The Meissner and Pacinian sensory corpuscles revisited new data from the last decade. Microsc. Res. Tech. 72, 299–309. Verdu, E., Buti, M., Navarro, X., 1996. Functional changes of the peripheral nervous system with aging in the mouse. Neurobiol. Aging 17, 73–77. Verdu, E., Ceballos, D., Vilches, J.J., Navarro, X., 2000. Influence of aging on peripheral nerve function and regeneration. J. Peripher. Nerv. Syst. 5, 191–208. Verdugo, R., Ochoa, J.L., 1992. Quantitative somatosensory thermotest. A key method for functional evaluation of small calibre afferent channels. Brain 115, 893–913. Verrillo, R.T., Bolanowski, S.J., Checkosky, C.M., McGlone, F.P., 1998. Effects of hydration on tactile sensation. Somatosens. Mot. Res. 15, 93–108.

99

Verrillo, R.T., Bolanowski, S.J., Gescheider, G.A., 2002. Effect of aging on the subjective magnitude of vibration. Somatosens. Mot. Res. 19, 238–244. Veyrat-Durebex, C., Alliot, J., 1997. Changes in pattern of macronutrient intake during aging in male and female rats. Physiol. Behav. 62, 1273–1278. Veyrat-Durebex, C., Alliot, J., Gaudreau, P., 2005. Regulation of the pituitary growth hormone-releasing hormone receptor in ageing male and female LOU rats: new insights into healthy ageing. J. Neuroendocrinol. 17, 691–700. Wang, L., Hilliges, M., Jernberg, T., Wiegleb-Edstrom, D., Johansson, O., 1990. Protein gene product 9.5-immunoreactive nerve fibres and cells in human skin. Cell Tissue Res. 261, 25–33. Weindruch, R., Masoro, E.J., 1991. Concerns about rodent models for aging research. J. Gerontol. 46, B87–B88. Wickremaratchi, M.M., Llewelyn, J.G., 2006. Effects of ageing on touch. Postgrad. Med. J. 82, 301–304. Woodman, C.R., Price, E.M., Laughlin, M.H., 2003. Selected contribution: aging impairs nitric oxide and prostacyclin mediation of endothelium-dependent dilation in soleus feed arteries. J. Appl. Physiol. 95, 2164–2170. Woodward, K.L., 1993. The relationship between skin compliance, age, gender, and tactile discriminative thresholds in humans. Somatosens. Mot. Res. 10, 63–67. Wu, M., Fannin, J., Rice, K.M., Wang, B., Blough, E.R., 2011. Effect of aging on cellular mechanotransduction. Ageing Res. Rev. 10, 1–15. Yang, S.H., Meta, M., Qiao, X., Frost, D., Bauch, J., Coffinier, C., Majumdar, S., Bergo, M.O., Young, S.G., Fong, L.G., 2006. A farnesyltransferase inhibitor improves disease phenotypes in mice with a Hutchinson-Gilford progeria syndrome mutation. J. Clin. Invest. 116, 2115–2121. Yang, Y.L., Loh, K.S., Liou, B.Y., Chu, I.H., Kuo, C.J., Chen, H.D., Chen, C.S., 2013. SESN-1 is a positive regulator of lifespan in Caenorhabditis elegans. Exp. Gerontol. 48, 371–379. Zahouani, H., Pailler-Mattei, C., Sohm, B., Vargiolu, R., Cenizo, V., Debret, R., 2009. Characterization of the mechanical properties of a dermal equivalent compared with human skin in vivo by indentation and static friction tests. Skin Res. Technol. 15, 68–76. Zhang, Z., Francisco, E.M., Holden, J.K., Dennis, R.G., Tommerdahl, M., 2011. Somatosensory information processing in the aging population. Front. Aging Neurosci. 3, 18. Zotterman, Y., 1939. Touch, pain and tickling: an electro-physiological investigation on cutaneous sensory nerves. J. Physiol. 95, 1–28.