The elderly, those older than 65 years of age, are the fastest growing segment of the American population [1]. At present, at 12.4% (35 million) of the total United States population, it is estimated that this group will comprise 20% (53 million) of the population by the year 2030 [2]. Moreover, trauma is the fifth leading cause of death for persons in the U.S. over the age of 65 [3]. Thus, it is clear that an understanding of the effect that aging plays on wound healing is of vital importance.

The first clinical description of impaired wound healing with age was recorded in the medical literature almost one hundred years ago [4]. Since that time, investigators have studied aspects of aging and wound healing ranging from the cellular level to the clinical level. In animal models of wound repair in the aged, there is a 20% to 60% delay in the rate of healing as compared to young animals [5]. The consensus is that the effect of aging on wound repair is primarily a temporal delay and not an actual impairment in the quality of healing [6].

Most literature on wound healing focuses on acute cutaneous wounds and will be the focus of this review. The principles of delayed and impaired wound healing that will be discussed are generally applicable to any organ system. The scant literature present on the healing of chronic wounds will be discussed. This review will summarize the changes seen in normal skin with aging. The effects of aging on the individual phases of healing will be examined. The effect of extrinsic influences (e.g., ultraviolet radiation, medical comorbidities) on wound healing will be detailed. Finally, recent clinical trials aimed at improving wound healing will be discussed.

Changes in Aging Skin

The German physician Rudolf Virchow first described the skin as a protective barrier for the internal viscera almost a century and a half ago [7]. It is now known that skin serves to protect against the entry of microorganisms, regulate water loss, protect against ultraviolet (UV) radiation, assist in thermoregulation, and as a component of the immune system [8]. The changes seen in aged skin are a combination of effects from intrinsic and extrinsic aging. Intrinsic aging is defined as the changes in skin that occur in sun-protected areas, independent of environmental insults. Extrinsic aging is comprised of the cumulative changes of long-standing environmental exposure, most notably to UV radiation from sunlight [9]. The sum effect of intrinsic and extrinsic aging is a progressive loss of function, increased vulnerability to the environment, and decreased homeostatic capability [10]. Clinically, aged skin is characterized by atrophy, drying, roughness, alterations in pigmentation, sagging, wrinkling, and the presence of benign and malignant tumors.

The epidermis, consisting mainly of squamous epithelial cells (keratinocytes), functions as a barrier against water entry. The thickness of the epidermis remains fairly constant with age [11], but there is a flattening of the dermal-epidermal junction, giving the appearance of atrophy [12]. In addition, the time for keratinocytes to migrate from the basal layer to the skin surface, a key process in repair, increases by 50% in aged individuals [13].

The dermis, comprised of fibroblasts and the extracellular matrix (ECM) (types I and III collagen, elastin, and glycosaminoglycans), is divided into the superficial papillary dermis and the deep reticular dermis. The papillary dermis forms ridges that maintain contact with the epidermis. With age, there is a flattening of these rete ridges, resulting in decreased surface contact between the dermis and epidermis [14]. This predisposes to separation of the dermal-epidermal junction with laterally applied tension [12]. The cellular content of the dermis, consisting of fibroblasts, mast cells, and macrophages, is decreased with age. Importantly, there is an age-related decrease in the number and function of antigen-presenting cells (e.g., Langerhans cells, mast cells) in aged skin [15]. The protein content of the dermis, primarily collagen, is decreased with age as well. This is the result of both decreased production and increased degradation [16]. The quality of the collagen that remains is altered, with fewer organized, rope-like bundles and a greater degree of disorganization seen. The quantity of elastin, a determinant of skin elasticity, is fairly constant with age. However, like collagen, elastin in the aged dermis displays a disordered morphology, resulting in decreased elasticity of the skin [17].

The microcirculation of the dermis is decreased with age, and this affects its ability to adapt to injury and changes in temperature. There is a marked reduction in cutaneous blood flow in aged as compared to younger humans [18]. Along with these changes in blood flow, dermal lymphatic drainage decreases with age, diminishing the ability to clear the wound of pathogens and also inhibiting wound contraction [19]. Age-related alterations in the dermal appendages result in decreased secretions from sweat and sebaceous glands, slowed hair growth, and diminished perception of pain and pressure [20, 21].

Most of the changes witnessed in aged skin are the result of long-standing sun exposure (UV light). Excessive exposure to sunlight results in sunburn and immune suppression in the acute setting and skin cancer and photoaging with chronic exposure [22]. As in intrinsically aged skin, the dermis is the site ofmost of the changes in photoaged skin [23]. Activation of matrix metalloproteinases (MMPs) by UV radiation results in disorganized collagen fibrils and the accumulation of abnormal elastin-containing materials [9].

Age-Related Changes in Phases of Healing

Although the process of wound healing is a continuum, it is classically separated into a series of overlapping phases for the ease of discussion (Fig. 1). During hemostasis a fibrin clot is formed at the site of endothelial injury and platelets aggregate. Platelets adhere to the injured endothelium and release chemokines, thereby attracting the cellular components of the inflammatory phase [24]. The inflammatory phase of wound healing is characterized by the presence of neutrophils, macrophages, and lymphocytes [25]. The inflammatory cells then serve to release proinflammatory cytokines (e.g., transforming growth factor [TGF]-α and interleukins) and growth factors (e.g., fibroblast growth factor [FGF] and vascular endothelial growth factor [VEGF]), ingest foreign materials, increase vascular permeability, and promote fibroblast activity [26, 27]. The proliferative phase begins several days after the initial injury. In this phase, capillary growth and granulation tissue formation occur. Cellular proliferation and abundant collagen synthesis by fibroblasts lead to re-epithelialization and construction of a preliminary dermis. The final phase of wound healing, resolution, is a long process of tissue remodeling and increasing wound strength. During this phase, type I collagen synthesis and turnover continues, and fibroblasts differentiate into myofibroblasts, allowing further wound contraction. These four phases (hemostasis, inflammation, proliferation, and resolution) have been studied in detail and exhibit characteristic changes with aging. Decreased levels of growth factors, diminished cell proliferation and migration, and diminished extracellular matrix secretion have been demonstrated.

Fig. 1.
figure 1

The process of wound healing is divided into four phases for ease of discussion.

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Alterations in Hemostasis and Inflammation

With endothelial injury, collagen is exposed, promoting the adherence of platelets to the injured endothelium. Platelet adherence to the endothelium is enhanced in aged subjects [28, 29]. Additionally, the release of alpha-granules, which contain TGF-β, TGF-α, and platelet-derived growth factor (PDGF), by platelets increases with age [30].

Conflicting conclusions have been drawn about the age-related alterations in the inflammatory phase of healing. Although some aspects of healing are depressed in this stage, others are enhanced. Decreased amounts of nitric oxide, a vasoactive mediator, are secreted by aged endothelial cells [31]. Accordingly, there is decreased capillary permeability at the site of injury, and the diapedesis of neutrophils is decreased. In contrast, leukocytes display an age-related increase in secretion of and response to many inflammatory mediators [32, 33, 34]. The infiltration of macrophages and B-lymphocytes into wounds is delayed in models of wound healing in middle-aged and elderly mice [6]. The arrival of T-lymphocytes to the wound bed is also delayed in aged animals, but the final level is increased as compared to young animals [15]. In aged animals, lymphocytes display a decreased proliferative response, a decreased number of naïve cells, and an increased number of memory cells [35, 36, 37]. Changes in macrophage function have been suggested to be critical to age-related repair defects. Young animals treated with an anti-macrophage serum prior to wounding heal at rates comparable to those of older animals [38]. Additionally, wound repair can be accelerated in aged mice by the intraperitoneal injection of macrophages harvested from young mice [39]. Accelerated wound repair was not seen with the injection of macrophages from old mice. Wound macrophages from aged animals display a decreased percentage of macrophages that are phagocytic, as well as a decreased phagocytic ability [15]. Production of growth factors by macrophages declines with age as well [40]. It can be concluded that there is an age-related decline in macrophage function.

Alterations in Proliferation

Keratinocytes, fibroblasts, and vascular endothelial cells display a reduced proliferative response in aged animals [41, 42]. Re-epithelialization, collagen synthesis, and angiogenesis all exhibit an age-related delay [40]. There is a general decrease in the number and size of dermal fibroblasts with age [43]. Aged fibroblasts have also been shown to exhibit a diminished response to growth factors and diminished replicative capacity [43, 44]. These changes result in an age-related delay in wound closure in animal models as well as in human wounds [45, 46, 47]. Whole wound studies have shown decreased rates of epithelialization and contraction in older animals [48, 49] and humans [50, 51, 52].

As the epidermis requires nutrition to migrate and proliferate, the process of angiogenesis is believed to be important for optimal wound repair [53]. Conflicting data are present in the literature, with the majority of studies indicating a decrease in angiogenesis with age [40, 54], and a few showing an increase [6, 55]. Excisional and subcutaneous implant models have been used to show that wound capillary ingrowth is delayed in aged animals [56, 57]. Reduced levels of the angiogenic factors FGF, VEGF, and TGF-β have been implicated as partially responsible for this delay [31, 40]. Indeed, replacement of these factors is able to reverse the delay [58].

The rate of collagen production, as measured by hydroxyproline content, is decreased with aging [59]. The decreased deposition of connective tissue has been shown to be primarily a deficit of type I collagen [42, 60]. Recent work has shown that while the deposition of collagen is delayed, the final collagen content in mature wounds does not differ in young and aged animals [40].

In laying down the new collagen framework, the existing ECM must be degraded, a process mediated by the matrix metalloproteinases (MMPs). The invasion of endothelial cells requisite for angiogenesis requires MMP activity as well [61]. Three types of MMPs—collagenases, stromelysins, and gelatinases—are secreted by keratinocytes and fibroblasts and can be found during wound healing [62]. The activity of MMPs is balanced by their naturally occurring inhibitors, the tissue inhibitors of metalloproteinases (TIMPs). Studies have shown that chronic non-healing wounds demonstrate an elevated level of MMP expression [63]. Additionally, delayed healing in the aged has been shown to result from an overexpression of MMPs, an underexpression of TIMPs, or both [64, 65, 66, 67]. Recent studies have shown that changes in MMP and TIMP expression with age are not global but rather are tissue and cell specific [41].

Alterations in Resolution

Young animals display a greater level of collagenase activity than older animals, allowing greater turnover and remodeling of newly formed collagen [68]. The hyperproliferative wound-healing disorders, hypertrophic scars and keloids, are rarely seen in aged wounds. Some evidence suggests that this may be due to decreased levels of circulating TGF-β [69]. Blockage of TGF-β, a molecule known to enhance collagen deposition, is able to prevent excessive scar formation in adults [70].

Most studies of the resolution phase of healing focus on wound strength as a measure of collagen content and cross-linking. Measurement of bursting strength is a classic method of studying wound strength [47, 54]. Studies of both intestinal anastomoses [71] and cutaneous wounds [72] have shown that older animals gain wound strength at a slower rate and have decreased strength as compared to younger animals. These findings have been shown to extend to human subjects; incisional wounds in patients over the age of 70 displayed lower tensile strength than those in patients younger than age 70 [73]. Laparotomy wound dehiscence is also more likely in patients over the age of 60 [74, 75]. The delay in wound closure also results in an increased incidence of infection and medical complications [74]. Unfortunately, these studies did not consider comorbidities common in the older population (e.g., diabetes, vascular disease).

Extrinsic Influences

With advancing age, concurrent medical disease and other factors that adversely effect wound healing become more common. Paramount to ensuring optimal wound healing is aggressive control of diabetes and vascular disease, which can impair granulation tissue formation. Corticosteroids, which inhibit lymphocyte function and collagen synthesis, should be withdrawn whenever possible [76, 77]. Alternatively, the deleterious wound healing effects of corticosteroids can be reversed with systemic administration of vitamin A [78, 79]. Poor nutritional status contributes to a delayed inflammatory response and delayed synthesis of matrix proteins and should be optimized [80]. Additionally, cigarette smoking impairs granulation tissue formation by the action of nicotine on the vascular system, and should be stopped [81].

Therapeutic Options

Although the studies on age-related alterations in wound healing discussed above have focused on acute wounds, clinical studies tend to focus on the treatment of chronic wounds (e.g., pressure ulcers, vascular insufficiency ulcers). Many studies over the last decade have examined the role of systemically or topically applied growth factors in wound healing. TGF-β1, basic FGF (bFGF), PDGF, and others have been shown to be of benefit in various animal models [31, 82, 83]. TGF-β1 applied to dermal wounds accelerated the rate of wound closure in aged rats [42]. It is difficult to know the mechanism by which the improved healing was effected, as TGF-β1 has multiple functional effects in the wound – attracting fibroblasts, enhancing collagen deposition, decreasing MMP-1 synthesis, and increasing TIMP-1 expression. Other studies have focused on the ability of topical estrogen to accelerate healing [84, 85]. Once again, the mechanism of this improvement is unclear, as the topical estrogen may be acting by increasing TGF-β1 expression [84]. Ultimately, results from studies in humans have been largely disappointing, and no clear recommendations on the use of growth factors can be made.

Due to overall disappointing results with the transition of a treatment option from animal studies to human studies, new models of aged wounds are being developed. Investigators have postulated that the primary defect in chronic wounds is local tissue hypoxia from scarring, fibrin cuffing, edema, increased venous pressure, and microvascular disease [86, 87]. Previously developed models have attempted to reproduce these conditions by the administration of glucocorticoids, exposure to ionizing radiation, or decreasing blood supply to the wound [88, 89, 90]. Recently, a model has been developed that uses rabbits aged 60 months to represent humans in the 7th and 8th decades of life [91]. Additionally, by interrupting the major arterial circulation as well as the dermal microcirculation to the wound, the setting of wound ischemia is created. In this model there is a profound impairment of granulation tissue formation and re-epithelialization. Additionally, this is the first animal wound-healing model in which treatment with TGF-β1 fails to promote healing. Further work has shown that this result is due to reduced expression of receptors for TGF-β as well as reduced activation of intracellular signaling pathways in response to TGF-β [92].

Other studies have examined the use of skin substitutes, electrical fields, vacuum devices, and supplemental oxygen, among other techniques in wound healing. Although no study has shown universal benefit, subgroups of patients have been shown to benefit with each of these techniques. Therapeutic approaches that may hold promise for the future of wound healing include gene therapy and the use of stem cells [93].

Summary

Through a combination of intrinsic and extrinsic aging, human skin undergoes a multitude of changes that can potentially affect the process of wound healing (Table 1). Each of the phases of healing demonstrates characteristic age-related changes as well (Table 2). When taken as a whole, it is reasonable to conclude that there are global differences affecting wound healing between young and aged individuals. It is therefore unlikely that a single therapeutic approach will serve to abrogate all of these changes. Future work should focus on therapies applicable to certain subpopulations of patients (e.g., those with venous or arterial insufficiency, immunosuppressed) that commonly develop chronic wounds. Additionally, more detailed model systems need to be developed to test potential therapeutic agents before they progress to clinical trials.

Table 1. Summary of the changes that take place in human skin with age.
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Table 2. Summary of the age-related changes in the individual phases of healing.
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Résumé.

Un défaut de cicatrisation chez les personnes âgées représente un problème clinique et économique majeur. Avec l’augmentation de la population âgée en nombre absolu et en pourcentage, on a besoin de comprendre les mécanismes derrière ces défauts de cicatrisation en rapport avec l’âge. La peau normale présente des caractéristiques qui changent avec l’âge ce qui a des implications dans la cicatrisation des plaies. De plus, le processus de cicatrisation chez le vieillard est altéré. Alors qu’autrefois, on considérait que la cicatrisation était défectueuse chez le vieillard, le consensus général aujourd’hui est que la cicatrisation n’est que retardée: le résultat final est qualitativement similaire à celle du sujet plus jeune.

Resumen.

La defectuosa cicatrización de heridas que se observa en los ancianos constituye un problema clínico y económico mayor. Con el crecimiento de la población de edad avanzada tanto en número como en porcentaje, se incrementa el interés en lograr una mejor comprensión de los mecanismos que determinan este defectuoso proceso relacionado con la edad. La piel normal preseneta cambios característicos relacionados con el avance de la edad que tienen implicaciones en cuanto a la cicatrización. Además, el proceso de cicatrización se ve alterado en las personas de edad avanzada. Aunque históricamente se ha considerado que la cicatrización es defectuosa en el anciano, ahora hay consenso en que la cicatrización está retardada, pero que el resultado final es cualitativamente similar al de personas más jóvenes.