Collagen and the aging skin

The Aging Skin and Collagen

Structure of Skin

Aging is a complex process which pertains to the whole body including the skin, which is characterized by atrophy of cells, decrease of tissue cell reserve and deterioration of capabilities to fulfil physiological cell functions. Aging runs in a similar way in different species which suggests that the process of aging is a deliberately programmed process, i.e., it is a result of the genetic code. It is conditioned by the deficiency to replicate of the last pair of chromosome at each division, which leads to shortening the end part of the chromosome and as a result the short telomers make transcription impossible and indicate aging of a cell and its apoptosis. The process of aging is also associated with damaging process of free radicals, which are constantly produced as a result of an aerobiccell metabolism. Despite cell antioxidant protection systems, free radicals continuously damage cell components and cause DNA as well as other biological particles damage. DNA damage and production of free radicals are also caused by exogenous environment factors, particularly by UV radiation. In women at the age of menopause estrogen receptors in the skin are not stimulated which is one of the major reasons of endogenous factors of skin aging, which overlaps aging pertaining to age and photo-aging [Zegarska, Woźniak, 2006].

The Skin

The skin is the largest organ of the human body; its surface is from 1.6 m3to 1.8 m3. The skin has variety of functions. Skin combines the human body from the external environment and also isolates from him.

Other functions of the skin:

  • The skin protects against external mechanical, physical, chemical and biological factors.
  • Skin is one of the organs responsible for maintaining a constant body temperature. In the process of thermo regulation are involved two mechanisms:
  1. The first one is related with the network of cutaneous blood vessels. It involves shrinking the blood vessels in case of a decrease in body temperature and thereby reduces blood flow through the skin tissue, preventing heat loss vasodilation. If the temperature rises, the blood flowing increase passing through the skin causing loss of excess heat.
  2. Another mechanism is related to the generation of sweat, which evaporates from the skin surface causes cooling of the body to prevent it from overheating.
  • The skin is an organ of sensation.
  •  It contains receptors and nerve endings.
  • The skin is involved in the synthesis of certain compounds such as vitamin D.
  • It participates in the metabolism of proteins, lipids and carbohydrates

Kinds Of Human Skin

There are two main kinds of human skin. Glabrous skin (non-hairy skin), found on the palms and soles, is grooved on its surface by continuously alternating ridges and sulci, in individually unique configurations known as dermatoglyphics. It is characterized by a thick epidermis divided into several well-marked layers, including a compact stratum corneum, by the presence  of  encapsulated  sense organs within the dermis, and by a lack of hair follicles and sebaceous glands. Hair bearing skin on the other hand, has both hair follicles and sebaceous glands but lacks encapsulated sense organs. There is also wide variation between different body sites. For example, the scalp with its large hair follicles may be contrasted with the forehead, which has only small vellus-producing follicles, albeit associated with large sebaceous glands. The axilla is notable because it has apocrine glands in addition to the eccrine sweat glands, which are found throughout the body [McGrath and others, 2008].

Structure Of The Skin

Any discussion of the structure of skin will necessarily refer to layers. The various layers of the skin work in concert to provide strength and flexibility and perform the multiple functions of the skin [Wickett, Visscher, 2006].

Human skin consists of a stratified, cellular epidermis and an underlying dermis of connective tissue. The dermal–epidermal junction is undulating in section; ridges of the epidermis, known as rete ridges, project into the dermis. The junction provides mechanical support for the epidermis and acts as a partial barrier against exchange of cells and large molecules. Below the dermis is a fatty layer, the panniculus adiposus, usually designated as ‘subcutaneous’. This is separated from the rest of the body by a vestigial layer of striated muscle, the panniculus carnosus [McGrath and others, 2008].

Figure 1 – The structure of skin – diagram shows different layers of skin [Malvi, 2011]


The typesof cells inthe epidermis:

Keratinocytes – also called pickle cells. Keratinocytes are living cells which, in the course of migration to the surface of the skin are subject to many changes and desquamation. These cells are actively involved in the process of keratinization of the epidermis. Keratinocytes by moving spinous and granular layer of the epidermis – and differentiate gradually changing its structure. During his journey are reactive keratosis, dehydration, and their metabolism gradually weakens and finally dies. The proteins of the first living cells of the epidermis are transformed into scleroproteins – horny protein containing mainly keratin. Keratin is resistant to chemical influences and insoluble in water. At the end of their journey keratinocytes are closely matched to each other very flattened keratinocytes. These cells are dead and resemble fish scales or closely stacked tiles on the roof . Keratinocytes constitute a horn filled with said plate epidermal keratin and other proteins ( invohirkina , filargina ) and adhered to each other strongly sticky adhesive fatty ( lipid ) .

Figure 2 – keratinocytes as seen under a microscope [Malvi, 2011]

Melanocytes – They make up 8% of the epidermis [Malvi, 2011] .Melanocytes are the pigment-producing cells . of the skin and hair in all mammals. In the skin, they are found at the basal layer of the epidermis at which they make pigment granules called melanosomes containing melanin. The melanosomes are transferred from the melanocytes to the epidermal keratinocytes at which they impart some protection to the cell nucleus from ultraviolet (UV) light and give the skin its color. The process of melanin synthesis and transfer of melanosomes occurs continuously as the epidermis renews but can be speeded up in response to UV exposure to produce tanning [Wickett , Visscher , 2006].

Figure 3 – Melanocytes [Malvi, 2011]

Langerhans Cells (LC)–  the fourth cellular component of the epidermis, are dendritic histiocytes, which begin migrating from their point of origin in the bone marrow toward the epidermis. LCs resemble melanocytes in that they lack intercellular bridges but differ from them in not belonging to the fixed epidermal cellular population. In their capacity as antigen- presenting cells, langerhans cells migrate from the skin to the regional lymph nodes.

Langerhans cells are designed to capture foreign particles settling and penetrating the skin. They contain motile immune cells initiating and supervising the process of destroying germs, toxins and so- called antigens irritating the skin.

Figure 4 – Langerhans Cells [Malvi, 2011]



Figure 5 – Merkel Cells [Malvi, 2011]

Merkel Cells – They are usually located in the deepest layer of the epidermis (germinal layer) [The Aging Skin]. Since they are furnished with desmosomes, it has been speculated that they may represent modified keratinocytes. Merkel cells are connected to synaptic ends of terminal nerve filaments called “Merkel disks”. These cells belong to the cutaneous neuroendocrine system and are believe to secrete chemical neurotransmitters in response to mechanical stimuli [Zappi, 2012].


Basic function of epidermis it is barrier function. The barrier function of the skin has been called “la raison d’etre” of the epidermis.The epidermal barrier serves to limit passive water loss from the body, reduce the absorption of chemicals from the environment, and prevent microbial infection. These defensive functions reside primarily in the top stratum of the epidermis, the stratum corneum (SC), at which they are integrated with SC formation and homeostasis.Thus, proper development and maintenance of the stratum corneum are keys to its remarkable ability to defend the body against both chemical and microbiologic attack as well as dehydration.

The epidermis is itself divided into several layers or strata starting with the basal layer or stratum basale just above the dermis proceeding upward through the prickle and the granular layers to the top layer, the SC. Figure 6 is a diagram representing the major strata of the epidermis [Wickett and Visscher, 2006].

Figure 6- Diagram of the epidermis showing the main layers. The clear layer (not shown) is only found in the very thick epidermis of the palms and soles [Wickett , Visscher ,2006].

Layers Of Epidermis

The epidermis can be divided into four (or five) distinct layers:

  1. stratum basale or stratum germinativum,
  2. stratum spinosum,
  3. stratum granulosum and
  4. stratum corneum
  5. (sometimes skin has 5 layers- the additional layer is called  stratum lucidum).

The term Malpighian layer includes both the  basal and spinous cells. Other cells that reside within the epidermis includes melanocytes, Langerhans’ cells and Merkel cells.

i) Stratum Basale (Basal cell layer) –It is a continuous layer that is generally described as only one cell thick, but may be two to three cells thick in glabrous skin and hyperproliferative epidermis. The basal cells are small and cuboidal (10–14 nm)  and  have  large,  dark-staining  nuclei,  dense cytoplasm  containing  many  ribosomes  and  dense  tonofilament bundles. Immediately above the basal cell layer, cytoplasm containing many ribosomes and dense tonofilament bundles. Immediately above the basal cell layer, the epibasal keratinocytes enlarge to form the spinous/ prickle-cell layer or stratum spinosum [Wickett , Visscher , 2006]..

ii) Stratum Spinosum (Prickle layer) –The prickle cell layer (stratum spinosum) consist of 8-10 layers of cells. The cells in these layers have lots of desmosomes, which anchor the cells to each other, and contain thick tufts of intermediate filaments (keratin). When the cell shrinks slightly, during fixation, the desmosomes from neighboring cells remain tightly bound to each other, and these connections look like ‘prickles’ or ‘spines’, hence the name prickle cells .

The stratum spinosum is succeeded by the stratum granulosumor granular layer because of the intracellular granules of keratohyalin. At high magnification, the  dense  mass  of  keratohyalin  granules  from  human epidermis  has  a  particulate  substructure,  with  particles of irregular shape on average 2 nm length and occurring randomly in rows or lattices. The cytoplasm of cells often upper, spinous layer and granular cell layer also contains smaller lamellated granules averaging 100 –300 nmin size, which are known as lamellar granules or bodies, membrane-coating granules or Odland bodies. These are numerous within the uppermost cells of the spinous layer and migrate towards the periphery of the cells as they enter the granular cell layer.  They discharge their lipid components into the intercellular space, playing important roles in barrier function and intercellular cohesion within the stratum corneum [Wickett, Visscher, 2006].

iii) Stratum Granulosum (Granular layer)–Granular layer is composed of several rows of cells with spindle-shaped nuclei strongly flattened. These cells are filled with grains keratohyalin, the immediate precursor of keratin. In cosmetology granular layer is identified with the so-called Rein barrier, responsible for skin impermeability to water

iv) Stratum Lucidum (Clear layer) – This layer is present only in those areas which are prone to friction i.e. in thick skin.  It is between the stratum granulosum and stratum corneum layer. It consists of large amount of keratin and thickened plasma membrane. The layer is made up of 3‐5 layers of flattened dead keratinocytes [Malvi, 2011]. This layer is also called a transition layer, since the cells can be distinguished from cells lying above bedan only by an electron microscope and special histochemical staining.

V) Stratum Corneum (Horny layer) – This layer consist of 25- 30 layers of cells- corneocytes which have lost nuclei and cytoplasmic oranelles. The cells become flattened and the  keratin  filaments  align  into  disulphide  cross-linked macrofibres, under the influence of filaggrin, the protein component  of  the  keratohyalin  granule,  responsible  for keratin  filament  aggregation..  The  corneocytes  has  a highly  insoluble  cornified  envelope  within  the  plasma membrane, formed by cross-linking of the soluble protein precursor, involucrin ,  following  the  action  of  a  specific epidermal transglutaminase also synthesized in the high stratum spinosum . The process of desquamation involves degradation of the lamellated lipid in the intercellular spaces and loss of the residual intercellular desmosomal interconnections [[McGrath and others, 2008]..

Figure 7 Micrograph of the upper dermis and epidermis showing the layers and major cell types. (Figure courtesy of Steve B. Hoath, MD, )

Figure 8 – Layers of epidermis: [B] = Stratum Basale, [S] = Stratum Spinosum, [G] = Stratum Granulosum, [C] Stratum Corneum [Malvi, 2011]


The dermis is the connective tissue component of the skin and provides its pliability, elasticity and tensile strength. It protects the body form mechanical injury, binds water, aids in thermal regulation and includes receptors of sensory stimuli. The dermis interacts with the epidermis in maintaining the properties of both tissues. The two regions collaborate during development in the morphogenesis of the dermal – epidermal junction (The dermal – epidermal junction is an example of a highly complex form of basement membrane, which underlies the basal cells and extends into the upper layers of the dermis)  and epidermal appendages, and interact in repair and remodeling the skin as wound are healed. The dermis is less cellular than epidermis, being composed primarily of fibrous and amorphous extracellular matrix surrounding the epidermal derived appendages, neurovascular networks, sensory receptors and dermal cells. The dermis does not undergo an obvious sequence of differentiation that parallels epidermal differentiation, but the structure and organization of the connective tissue components are predictable in adept dependent manner. The matrix components undergo turnover and remodeling in normal skin, in pathological processes and in response to external stimuli [Freinkel, Woodley, 2001].

Dermis is composed mainly of connective tissues containing collagen and elastic fibers. Cells present in dermis include: ‐

Fibroblast – The primary cell type of the dermis is the fibroblast, a mesenchymally derived cell that migrates through the tissue and is responsible for the synthesis and degradation of fibrous and non- fibrous connective tissue matrix proteins and a number of soluble factors. The same fibroblast is capable of synthesizing more than one type of matrix protein simultaneously (e.g. collagen and elastin). Fibroblasts are highly diverse population. Even within a single tissue phenotypically distinct population exist. Studies of human fibroblast cell lines support a sequence of fibroblast differentiation that involves a series of stem cells that become progressively committed to a reportire of cells, each of which gives rise to a series of mitotic progenitor cells that in turn differentiate into cells that ultimately undergo degeneration or transformation. There is a great interest in fibroblast regulation because of increased proliferative and synthetic activity in wound healing and during formation of hypertrophic scars [Freinkel , Woodley , 2001].

Figure 7 – Fibroblasts [Malvi, 2011]

Macrophages – Macrophages are derived from precursor cells of the bone marrow that differentiate into monocytes in the blood, then migrate into the dermis where they differentiate. Macrophages are difficult to distinguish morhologically from fibroblast if they do not contain lysosmes and phatogenic vacuoles, because both cell types can have well- developed rough endoplasmic reticulum and Golgi aparatus, intermediate filaments in the cytoplasm and occupy similar locations in the tissue. Macrophages have an expansive list of functions in the skin; they are phagocytic; they process and present antigen to immunocompetent lymphoid cells; are microbicidal (through the production of lysozyme, peroxide and superoxide), tumoricidal, secretory (growth factors, cytokines and other immunomodulatory molecules) and hematopoietic; and they are involved in coagulation, atherogenesis, wound healing and tissue remodeling [Freinkel , Woodley , 2001].

Figure 8 – Macrophages [Malvi, 2011]

Adipocytes –They have three primary functions. Fat cells are insulin sensitive, they store lipid, and they secrete hormones that act in distant tissues. Of note, the disruption of any one of these adipocyte functions results in an unhealthy metabolic disease state that increases risk for type 2 diabetes. Hormones that are produced exclusively in adipocytes, such as leptin and adiponectin, have various functions including the regulation of food intake and modulation of sensitivity to insulin, a hormone involved in regulating blood glucose levels . There are different types of adipocytes that are broadly classified into three main types based, in part, on the color of the fat tissue: white, brown, or beige. The overall function of white adipocytes is to store energy, while the function of brown adipocytes is to dissipate energy in a heat-producing process called thermogenesis. The function and origin of beige cells is less clear and under intense investigation. [Stephens, 2012].

Figure 9 – Adipocytes [Malvi, 2011]

Structural organization of the dermis

Two distinct regions can be identified within the dermis: the uppermost papillary dermis and the lower reticular region. The distinction is based largely on their differences in connective tissue organization, cell density and nerve and vascular patterns. A horizontal plane of vessels, the sub papillary plexus, marks the boundary between the papillary and reticular dermis. The deep boundary between the dermis and the hypodermis is defined by the transition from fibrous to adipose connective tissue [Hake, Holbrook, 1999].

Papillary region – The papillary dermis is characterized by small bundles of small diameter collagen fibrils and oxytalan elastic fibers. The presence of mature elastic fibers usually not found in the normal papillary dermis is indicative of certain inherited connective tissue diseases, aged or actinically damaged skin. The structural characteristics of the matrix in the papillary dermis permit the skin to accommodate to mechanical stress. The region also has a high density of fibroblastic cells that proliferate more rapidly, have a higher rate of metabolic activity than those of the reticular dermis and synthesize different species of proteoglycans. Capillaries extending from the sub papilary plexus project toward the epidermis within the dermal papillae, finger like projections of papillary dermis that interdigitate with the retepegs that project from the epidermis into the dermis [Freinkel, Woodley, 2001]. Some dermal papillae contain tactile receptors called corpuscles of touch or Meissner corpuscles these are nerve endings that are sensitive to touch. Also present in dermal papillae are free nerve endings which initiate signal which gives rise to sensation of warmth, coolness, pain, tickling and itching [Malvi, 2011].

Reticular region – It is the deeper part of dermis. The reticular dermis is composed primarily of large- diameter collagen fibrils organized into large, interwoven fiber bundles. Mature, band like, branching elastic fibers form a superstructure around the collagen fiber bundles. These two fiber systems are integrated, providing the dermis with strong and resilient mechanical properties. In normal individuals the elastic fibers and collagen bundles of the reticular dermis increase in size progressively toward the hypodermis [Freinkel, Woodley, 2001]. Adipose cells, hair follicles, nerves, sebaceous glands, sweat glands occupy the space between the fibers. Combination of collagen and elastic fibers in reticular region is responsible for providing the skin with strength, extensibility and elasticity [Malvi, 2011].

Subdivision of the reticular dermis into an upper intermediate zone and a deeper zone is possible because of graded differences in the size and character of the fibrous connective tissue. Intermediate-sized collagen fibrils and fiber bundles and horizontally oriented elaunin elastic fibers characterize the upper zone of the reticular dermis. This zone also has distinct mechanical properties compared with the deeper dermis; it is particularly susceptible to cleavage following trauma, and it may be involved in disease processes (e.g., selective loss of elastic fibers) when other regions are not. [Freedberg I. and others, 2003].

Dermal connective tissue matrix

Collagen and elastic connective tissue are the main types of fibrous connective tissue of the dermis. There are also non- fibrous, connective tissue molecules, including the filamentous glycoproteins and the proteoglycans and glycosaminoglycans of the ‘ground substance’ [Freinkel, Woodley , 2001].

Dermal matrix components

I] Collagen is the major dermal constituent.  It accounts for approximately 75 percent of the dry weight of the skin, and provides both tensile strength and elasticity.

Three main classes of collagens are present normally in connective tissue: fibrillar collagens (types I, III, and V), basement membrane collagen (type IV), and other interstitial collagens (types VI, VII, and VIII). These are merely examples of the many different types of collagen present in skin [Freedberg and others, 2003]

Type I collagen, the most widely distributed and most extensively characterized form of collagen, is found predominantly in bone and tendon and it accounts for approximately 80 percent of the total collagen of adult human dermis. The type I collagen molecule contains two identical a chains, designated a1(I), and a third chain, called a2 (I), clearly different in its   amino acid composition. Thus, the chain composition of type I collagen is [a1 (I)] 2a2 (I). Collagen molecules that consist   of three identical a1(I) chains have also been detected, but these so-called a1(I) trimer molecules with chain composition of [a1(I)] 3 appear to represent a minor fraction of collagen in connective tissues, such as the skin. 9 Collagen types I and III form the relatively broad extracellular fibers that are primarily responsible for the tensile strength of the human dermis. Mutations in the type I and III collagen genes can result in connective tissue abnormalities in the skin and joints, among   other tissues, in different forms of the Ehlers-Danlos syndrome and fragility of bones in osteogenesis imperfect [Freedberg and others, 2003].

II] Elastin‐ Elastic fibers of the connective tissue form a network responsible for the resilient properties of various organs and the distribution of elastic fibers is variable in different tissues. Their relative concentration is highest in the aorta and arterial blood vessels, but they are also abundant in the lungs. Elastic fibers are also present in the skin, although they are only a minor component. Specifically, in sun protected human skin, the elastin content is about 1 to 2 percent of the total dry weight of dermis. In the papillary dermis, elastic fibers are present either as bundles of microfibrils (oxytalan fibers) or with small amounts of cross-linked elastin (elaunin fibers). In the reticular dermis, the elastic fibers, which consist primarily of elastin, are oriented horizontally in a network with vertical extensions to the papillary dermis in the form of oxytalan fibers [Freedberg and others, 2003].

III] Glycosaminoglycans‐ It is a constituent of the dermal skin along with collagen and elastin and is responsible for conferring the outward appearance of the skin [Malvi, 2011].Glycosaminoglycans (GAGs) are polysacchride chains composed of repeating dissacchride units. GAGs have high degrees of heterogeneity with regard to chain length and disaccharide composition. GAGs comprise hyaluronic acids and are constituents of proteoglycans. Hyaluronic acids are composed of unsulfated and branched GAGs with molecular weights ranging from 10 to 104 kDa. Hyaluronic acids function as ground substance to fill space in extracellular matrix (ECM), are particularly abundant in skin and joints. Proteoglycans consist of sulfated GAGs covalently linked to core proteins and have diverse localizations, such as cell surface, basement membrane and ECM. Interstitial proteoglycans found in ECM can be classified into large aggregated proteoglycans (LAPs) and small leucine rich proteoglycans (SLRPs). LAPs consist of large core proteins (more than 100 kDa) and numerous GAGs and usually form large aggregates with hyaluronic acids. Four LAPs, including versican, aggrecan, brevican and neurocan are found in ECM of various connective tissues. SLRPs form a growing, heterogeneous subfamily of proteoglycans, which are able to bind with a variety of proteins, including ECM proteins, particularly type I collagen.[Li and others, 2013]

Cutaneous Aging and its Causes

Cutaneous Aging

Cutaneous aging is a complex biological phenomenon consisting of two components:

  • intrinsic aging
  • extrinsic aging.

Intrinsic aging is also termed true aging which is an inevitable change attributable to the passage of time alone and is manifested primarily by physiologic alterations with subtle but undoubtedly important consequences for both healthy and diseased skin and is largely genetically determined.

Extrinsic aging is caused by environmental exposure, primarily to UV light, and more commonly termed photoaging. In sun-exposed areas, photoaging involves changes in cellular biosynthetic activity that lead to gross disorganisation of the dermal matrix. The intrinsic rate of skin aging in any individual can be dramatically influenced by personal and environmental factors, particularly the amount of exposure to ultraviolet light. Photodamage, which considerably accelerates the visible aging of skin, also greatly increases the risk of cutaneous neoplasms. So, the processes of intrinsic and extrinsic aging are superimposed [Farage, Miller, Maibach, 2010].

Causes of Aging

Telomere Shortening

The terminal portions of eukaryotic chromosomes are termed telomeres. In all mammals, they are composed of repeats of the short DNA sequence TTAGGG and in man are several thousand bases in lenght. Telomeres appear to protect the chromosomes shorten each round of DNA replication, and the presence of telomeric repeats at the chromosome ends prevents loss of critical- coding sequences. Finally, by shortening with each round of cell division, telomeres serve the biological clock, informing cells thta they are young or old. Both epidermal keratinocytes and dermal fibroblasts from older individuals have shorter telomeres than do younger individuals have shorter telomeres than do such a Werner’s syndrome and progeria, are shorter than those of age- matched controls. Germline cells as well as immortalized cell lines and almost all malignant cells expres the enzyme telomerase that adds beses to telomeres and thus maintains their lenght, despite repeated cell divisions. Incontrast, somatic cells generally lack this enzyme and have a finite proliferative ability [Lim, Honigsmann, Hawk, 2013].

One implication of this theory places aging and cancer on opposite sides of the same coin. That is, telomerase, the cellular reverse transcriptase enzyme that stabilizes or lengthens telomeres, is expressed in about 85–90% of all human tumors but absent in many somatic tissues. Consequently, most cancer cells, unlike healthy ones, are not programmed for apoptosis, or cell death. In other words, the presence of telomerase is associated with telomere stability and tumourigenesis, its absence with telomere shortening and somatic tissue aging.

Indeed, the natural, progressive shortening of telomeres may be one of the primary mechanisms of cellular aging in skin. Telomeres and other cellular constituents also sustain low‐grade oxidative damage as a result of aerobic cellular metabolism, which contributes to intrinsic aging.

Currently, there are no available topical skin care products, systemic drugs or other treatment options that target telomerase since experimental data does not adequately demonstrate that extending telomere length can be safely performed. One argument for eventual telomerase‐based therapies is the belief that inhibiting telomerase may also have antiproliferative and apoptosis‐inducing effects, not related to the role this ribonucleoprotein plays in shortening telomeres during cell division [Malvi, 2011].

A recent research proposes that telomere function is determined by more than just lenght. Telomere ends appear to exist in a “capped” (hidden) or “uncaped” (exposed) form and, when uncapped, cause DNA damage response in the cell. It is known that telomeres are normally present in a loop configuration and that the loop is held in place by the final 150 to 200 base of the TTAGG repeats on the 3′ strand that forms a single- stranded overhang and insert into the proximal telomeric double helix. Further, when the loop is disrupted experimentally, the overhung is digested and the cell mounts DNA damage responeses, including entry into sensence in some cell types. It was reported that oligonucleotides homologous to the telomere overhang sequence (“T- oligos”) are taken up into the cell nucleus and cause identical responses. These findings suggest that the physiological signal for cells to enter senescence following acute DNA damage or critical telomere shortening may be exposure of the TTAGG overhang sequence, an event mimicked by T- oligos in the absence of telomere disruption. In all instances, the responses are mediated by the same molecular pathways, centrally involving the tumor supressor protein p53 [Lim, Honigsmann , Hawk, 2013].

Mitochondrial Damage

Mitochondria are organelles whose main function is to generate energy for the cell. This is achieved by a multistep process called oxidative phosphorylation or electron transport chain. Located at the inner mitochondrial membrane are five multiprotein complexes that generate an electrochemical proton gradient used in the last step of process to turn ADP and organopfhosphate into ATP. This process is not completely error- free and ultimately leads to the generation of reactive oxygen species (ROS), making the mitochondrion the site of the highest ROS turnover in the cell. [Farage, Miller, Maibach  ,2010].

Endocrine Dysfunction

It is observed that with age there is reduction in the production of hormones. Estrogen is one such hormone the production of which reduces with age and lower levels of estrogen are associated with skin aging and telomere shortening. The effects of reduced estrogen level causes loss of elasticity, reduced water holding capacity, increased pigmentation and decreased vascularity[ Malvi, 2011].

The main biological effects of estrogen on the skin of postmenopausal women with regard to skin thickness, moisture, wrinkling, wound healing, and scarring, and briefly discusses future estrogen therapies, such as selective estrogen receptor modulators (SERMs).

Studies have uncovered various mechanisms by which estrogen may effect skin aging and function. Research indicates that topical and systemic ERT (estrogen replacement therapy) lead to a statistically significant improvement in many aging skin problems. Estrogen replacement therapy increases skin collagen content and preserves thickness, thereby reducing wrinkling. Skin moisture content improves with ERT, as it increases the skin’s hyaluronic acid, acid mucopolysaccharides, and sebum levels, and possibly maintains stratum corneum barrier function.

Beyond its impact on aging, topical estrogen replacement therapy accelerates and improves cutaneous wound healing in elderly individuals, possibly by regulating the levels of a cytokine. Conversely, a lack of estrogen (i.e., hypoestrogenism) or addition of tamoxifen – the first SERM developed – may improve the quality of scaring, though the relationship between estrogen and scarring is more ambiguous [Farage, Miller, Maibach, 2010]


Among all environmental factors, solar UV radiation is the most important in premature skin aging, a process accordingly termed photoaging. Over recent years, substantial progress has been made in elucidating the underlying molecular mechanisms. From these studies, it is now clear that both UVB (290- 320 nm) and UVA (320- 400 nm) radiations contribute to photoaging. UV- included alternations at the level of the dermis are best studied and appear to be largely responsible for the phenotype of photoaged skin. It is also generally agreed that UVB acts preferentially on the epidermis where it not only damages DNA in keratinocytes and melanocytes, but also causes the production of soluble factors including proteolytic enzymes, which in a second step affect the dermis; in contrast, UVA radiation penetrates far more deeply on average and hence exerts direct effects on both the epidermal and the dermal compartment (Figure). UVA is also 10- 100 times more abundant in sunlight than UVB, depending on the season and time of the day [Farage, Miller, Maibach, 2010].

Skin aging caused by sun exposure can occur even before intrinsic aging. The changes that are observed due to photoaging are leathery appearance with wrinkle formation, impaired wound healing, appearance of lesions on the skin such as actinic and seborrheic keratoses, cutaneous horns, skin cancer, pigmentary alterations such as lentigens and hyperpigmentation and the most prominent feature is elastosis. The ultraviolet rays from the sun causes skin damage and accelerate aging of the skin [Malvi, 2011].

Fig 10.  Wavelenght- dependent penetration of UV radiation into human skin

There are 2 mechanisms by which the ultraviolet radiations act:

Induction of matrix metalloproteinases 

UV irradiation induces expression of certain members of the matrix metalloproteinase (MMP) family, which degrade collagen and other extracellular matrix proteins that comprise the dermal connective tissue [Quan and others, 2009].

MMPs comprise a family of zinc-containing proteinases that are responsible for degrading ECM (Extracellular matrix) proteins, which form skin dermal connective tissue. To date, the MMP gene family consists of 25 members, 24 of which are expressed in mammals. MMPs are classified as collagenases, gelatinases, stromelysins, and membrane-type MMPs according to their substrate specificities and depending on whether they are secreted as soluble proteins or bound to cell surface membranes. MMPs are involved in a wide range of proteolytic events in physiological and pathological circumstances, including embryogenesis, wound healing, inflammation, angiogenesis, and cancer.

Studies conducted by scientist [Quan and others, 2009] and by others over the past several years have revealed that UV radiation elevates at least three different MMPs in human skin in vivo, which is interstitial collagenase (MMP-1), stromelysin-1 (MMP-3), and 92-kDa gelatinase (MMP-9). These three MMPs are strongly regulated by transcription factor activator protein-1, which is rapidly induced and activated by UV radiation in human skin in vivo . The combined actions of MMP-1, -3, and -9 have the capacity to degrade most of the proteins that comprise the dermal ECM [Quan and others, 2009].

ii) Ultraviolet Induced Mitochondrial Damage‐ Ultraviolet radiations can cause mitochondrial damage in three ways:

Mitochondrial DNA Damage: 

Photoaged skin is characterized by increased mutations of the mitochondrial genome. Intra individual comparison studies have revealed that the so- called common deletion, a 4,977- bp deletion of mtDNA, is increased up to tenfold in photoaged skin as compared with sun protected skin of the same individuals. The amount of the common deletion in human skin does not correlate with chronological aging, and it has therefore been proposed that mtDNA mutations such as the common deletion represent molecular markers for photoaging. In support of this concept it has been shown that repetitive, sub lethal exposure to UVA radiation at does that may be acquired during a regular summer holiday induces mutations of mtDNA in cultured primary human dermal fibroblasts in a singlet oxygen- dependent fashion. Even more importantly, in vivo studies have revealed that repetitive exposure three times daily of previously unirradiated buttock skin for a total of 2 weeks to physiological doses of UVA radiation leads to an approximately 40% increase in the levels of the common deletion in the dermal, but not the epidermal compartment of irradiated skin [Quan and others, 2009].

Production of Reactive Oxygen Species: The Ultraviolet radiations are capable of exciting electrons in the outermost shell of the oxygen atom to a higher energy level. This excitation can cause the oxygen molecule in cells to split into the oxygen free radical [Malvi, 2011].

Both UVB and UVA can be absorbed by cytoplasmic ring- containing molecules such as NADH, riboflavin quinones, tryptophan and tyrosine, and the heme group of catalase. The resulting energetic molecule can interact with DNA to produce a T- containing cyclobutane dimer or can produce reactive oxygen species. In the latter pathway, the chromophore’s energy is transferred to oxygen, resulting in singlet oxygen (O2; an excited state of oxygen) or, if an electron is transferred, superoxide (O2 • ). In the presence of water, these lead to hydrogen peroxide (H2O2) and thence, in the presence of Fe 2+, to the hydroxyl radical ( • OH). Hydroxyl radicals produce oxidative DNA damage resembling that after gamma radiation. Reactive oxygen species react with lipid membranes and the redox- sensitive catalytic site of phosphatases [Farage, Kenneth, Maibach, 2010].

Formation of uncommon Dβ Aspartyl residues: UV radiations lead to the formation of D‐β‐ Aspartyl residues in the elastic fibers of the skin. These uncommon D‐β‐ Aspartyl residues have been reported in proteins of various elderly tissues [Malvi, 2011].

Scientist[Fuji and others, 2002] try tosolve this problem.For this purpose,the polyclonal antibody against d-β-Asp-containing peptideis designed. The authors of research believe that the molecule could be a useful indicator for sun damage of the skin. The antibody recognized integrated or disintegrated elastic fibers in the sun-exposed skin but not in the sun-protected skin of the elderly donors. The results of research suggest that UV irradiation is closely related to the formation of D-β-Asp in the elastic fibers of skin.


Already in the ’70 scientists reported that smoking has deleterious effects on the skin and that wrinkles are typical clinical features of smokers. A recent epidemiological study provides that tobacco smoking is one of the most important factors contributing to premature skin aging. Using silicone rubber replicas combined with computerized image processing, the association between wrinkle formation and tobacco smoking has been investigated. The variance and depth of furrows in subjects with a history of smoking 35 pack- years or more were significantly greater than in non- smokers.

Molecular mechanisms of tobacco smoke, including damage is still poorly understood. In general tobacco smoke acts via mechanisms similar to those identified for UV radiation. These include a decrease of collagen and an increase in tropoelastin content of the skin, alternations in proteoglycan expression, and induction of MMPs [Gilchrest, Krutmann, 2006].


The lifestyle of a person can also contribute to the aging skin. Factors such as lack of sleep, alcohol consumption, stress, improper diet, and reduced intake of water, can all lead to minor signs of aging [Malvi, 2011].

Characteristics of the Aging Skin

The changes undergone by skin as it ages, occurs throughout the epidermis, dermis and the subcutaneous tissue.

Figure 11 – A histological comparison of the skin. To the left is the histological section of a young person, while to the right is the histological section of the skin of an aged person [Malvi, 2011].

Photodamage affects both the epidermis and the dermis. In contrast to chronologically aged skin, photodamaged epidermis is frequently acanthosis, although as discussed above, severe atrophy also can be seen. The epidermis displays, in addition, loss of polarity and cellular atypia. Also, there is a decrease in the number and function of Langerhans cells [Lim, Honigsmann , Hawk, 2013].

Epidermal Changes

Epidermal changes associated with aging involve the flattening of its underside, a reduction in the number of Langerhans cells and of melanocytes, and a decline in the number of melanosomes synthesized, leading to reduced pigmentation [Howard D.].

As we grow older, the skin becomes drier, rougher and less able to retain moisture. Age- related skin changes start at about the age of 30 and result in decreased protection and increased susceptibility to injury, slower healing, reduced barrier protection and delayed absorption of drugs and chemical placed on the skin.

Damage to the skin can be seen through skin tears caused by the simplest measures such as the removal of plasters or dressings. A decrease in the levels of estrogen and progesterone, associated with aging, influence the process of drying and thinning of skin causing the skin to appear pale and trasculent. Blisters can also form easily as we age due to these aging changes. The skin becomes drier and rougher due to a reduction in the amount of moisture present in the stratum corneum.

Increasing age is responsible for a reduction in the rate of turnover of cells in the epidermis. There are fewer basal cells being replaced and the basal cells decreases by about 50% between the third and seventh decades of life and results in the epidermis thinning with age. Thinning of the skin is also influenced by flattening of the epidermal- dermal interface. This area of contact between the epidermis and dermis decreases with age, resulting in easy separation of these layers and increasing fragility of the skin. Increasing amounts of moisture escapes from the skin due to the thinning of the epidermis. The skin becomes less flexible, elastic fibres lose some of their elascticity and collagen fibres become increasingly tangled. The number of fibroblast, which are the cells responsible for the synthesis of protein and collagen, tends to decrease. All these changes result in the dry and wrinkled skin apperance found in older people. Also the number of Langerhans cell decrease with age. This reducton in cells decreases the overall effectiveness and responsiveness of the immune system [ Farley A., 2011].

Dermal Changes

The dermis displays loss of mature collagen and the remaining collagen shows basophilic degeneration. Also, there is a reduction of density of anchoring fibrils affecting epidermal adhesion to the dermis. A major component of photodamaged demis is elastosis, a material characterized histologically by tangled masses of degraded elastic fibers that further deteriorate to form an amorphous mass composed of disorganized tropoelastin and fibrillin. Although fibrillin is abundant in the elastotic material deeper in the dermis, in the upper portions of the dermis at the dermo- epidermal junction, fibrillin is reduced. The amount of ground substance, largely composed of glycosaminoglycans and proteoglycans, increases in photodamaged dermis. In contrast to aged sun- protected skin that demonstrates hypocellularity, photodamaged skin frequently displays inflammatory cells, including mast cells, histiocytes, and other mononuclear cells, giving rise to the term heliodermatitis (literally, ” cutaneous inflammation due to sun”). Fibroblasts are also more numerous in photodamaged skin than in aged sun- protected skin and display an irregular stellate shape. [Lim, Honigsmann, Hawk, 2013]

Associated with age, the dermis decreases in density, loses cells and has a reduction in the number of blood vessels within it. As with the epidermis, dermal collagen volume reduces with age. The total amount of collagen decreases by 1% per adulthood year. Collagen thickens, becomes less soluble and more resistant to digestion by the enzyme collagenase. This thickened collagen is less pliable with the effects of aging and as such predisposes the dermis to tear- type injury. Elastic fibres within the dermis also lose extensibility and contractibility. A consequence of which is skin sagging and wrinkling [ Farley A., 2011].


Collagen is among the most abundant fibrous proteins and fulfills a variety of mechanical functions, particularly in mammals. It constitutes the major part of tendons and ligaments, most of the organic matrix in bone and dentin; it is present in skin, arteries, cartilage and in most of the extracellular matrix in general [Fratzl, 2008]

The role of damaged collagen in skin aging

It has been demonstrated that exposure of cultured fibroblasts from either photodamaged or sun- protected skin to partially degraded type I collagen (produced by in vitro treatment of collagen with a mixture of MMPs from human skin) inhibits procollagen syhthesis. Among collagen fragments, not small ones but larger breakdown fragments of type I collagen negatively regulate its synthesis, suggesting that the high- molecular- weight fragments of type I collagen serve as negative regulators of type I collagen synthesis and that further degradation of MMP- 1- cleaved collagen by MMP-9 can alleviate this inhibition.

Thus, UV- induced MMPs damage the dermis by two related mechanisms: direct degradation of collagen and indirect inhibition of collagen fragments found in photoaged skin are also likely to be operative in aged skin and are superimposed on an intrinsic decline in collagen synthetic ativity. The role of MMP- damaged collagen in inhibiting new collagen synthesis in vivo is not known. However, since the rate of collagen synthesis is proportional to the level of mechanical tension, we speculate that damaged collagen fibrils are more pliable than native fibrils. As fibroblasts interact with damaged collagen collagen fibrils, the cells experience less resistance and therefore less mechanical tension, resulting in reduced procollagen synthesis [Rigel and others,  2004 ] .

Alterations in collagen, the major structural component of skin, have been suggested as a cause of the clinical changes observed in photoaged and naturally aged skin. The dermis contains predominantly type I collagen (85%-90%) with lesser amounts of type III collagen (10%-15%). Dermal fibroblasts synthesize the individual polypeptide chains of types I and III collagen as precursor molecules called procollagen. During the formation of insoluble collagen fibrils, specific proteases cleave the carboxy and amino terminal domains, giving rise to pN collagen (procollagen from which the carboxy terminal propeptide has been cleaved) and pC collagen (procollagen from which the amino terminal propeptide has been cleaved), respectively. Because type I and type III procollagen, pN collagens, and pC collagens are precursor molecules of mature collagen, their levels generally reflect the level of collagen biosynthesis.

have shown that UV irradiation induces the synthesis of matrix metalloproteinases (MMP) in human skin in vivo. They proposed that MMP-mediated collagen destruction accounts, in large part, for the connective tissue damage that occurs in photoaging. In addition, the same group of investigators reported that type I and type III procollagen levels are significantly lower in severely photodamaged human skin. Thus, they claimed that collagen synthesis is reduced more in photoaged human skin than in naturally aged skin in viv. Recently, it has been suggested that collagen damage due to natural skin aging may arise, as it does in photoaging, from elevated metalloproteinases expression with a concomitant reduction in collagen synthesis.Scientists reported that with increasing age MMP levels become higher and collagen synthesis becomes lower in sun-protected human skin in vivo [Chung and others, 2001].

In the last 15 years, the pathogenesis of UVR induced collagen damage has been well understood and characterized. For instance, it is known that UVR exposure significantly up- regulates the synthesis of several types of collagen- degrading enzymes known as matrix metalloproteinases (MMPs). First, UV exposure leads to an increase in the amount of the transcription factor c- jun; cfos, the other transcription factor involved in this mechanistic chain, is already abundant without UV exposure. Activator protein- 1 (AP-1) is then formed by the combination of c- jun and cfos. Changes in AP- 1 activity due to changes in the expression of AP- 1 family members, post- translational modification, or both occur in response to a wide variety of signals including UV light. In turn, AP- 1 activates the MMP genes, which stimulate the production of collagenase, gelatinase and stromelysin. Collagen degradation is mediated by AP- 1 activation and by inhibition of transforming growth factor (TGF)β signaling [Lim, Honigsmann, Hawk ,2013; Malvi, 2011].

Research in humans has shown that within hours of UVB exposure, MMPs, specifically collagenase and gelatinase, are produced. Multiple exposures to UVB engender a sustained induction of MMPs. Given that collagenase attacks and degrades collagen, long‐term elevations in the levels of collagenase and other metalloproteinases s likely yield the disorganized and clumped collagen identified in photo‐aged skin. Notably, these MMPs may represent the mechanism through which collagen I levels decline in response to UV exposure.

By characterizing the wide‐ranging effects of UV in activating cell surface growth factor and cytokine receptors, researchers have been able to ascertain that skin aging (extrinsic and intrinsic) is marked by elevated AP‐1 activity and MMP expression, inhibited TGFβ signaling, as well as reduced collagen synthesis and greater collagen degradation. These changes are likely to be exacerbated by photo‐aging [Malvi, 2011].


Elastin is a resilient connective tissue in the extracellular matrix. Elastin fibers are found at the periphery of collagen bundles and endow the skin with rebounding properties.  Tropoelastin molecules, which are precursors to elastin, bind covalently with cross-links to form elastin. Elastin fibers are assembled on bundles of microfibrils composed of fibrillin. The latter forms a template on which elastin is deposited.

Most elastin production is restricted to a narrow window of development. Elastogenesis increases dramatically during fetal life, peaks near birth and early neonatal life, decreases significantly thereafter, and is nearly nonexistent by maturity.In contrast to collagen fibers, elastin fibers are present in various stages of maturity. Oxytalan fibers, the least mature  elastin  fibers,  course  perpendicularly  from  the dermal-epidermal  junction  to  the  top  of  the  reticular dermis whereas elaunin fibers, the more mature elastin fibers,  attach  to  a  horizontal  plexus  of  fibers  found  in the  reticular  dermis.  Elaunin fibers are more mature because they have more elastin deposited on the fibrillin mesh. The most mature elastin fibers are unnamed and are found deeper in the reticular dermis.

This fibrous network running from the uppermost section of the papillary dermis to just beneath the basement membrane lends elasticity to young skin.  As  this  network deteriorates  with  age,  the  loss  of  or  damage  to  elastin fibers may play a significant role in skin sagging and loss of youthful resilience.

Photoaging initially leads to hyperplasia of elastin fibers according to the level of UV exposure. Later, a degenerative response occurs with resultant loss of skin elasticity. When viewed by light microscopy, degraded elastin appears as an amorphous substance that accumulates in the papillary dermis.

The resultant elastosis, a hallmark of  photoaged  skin,  is  due  to  the  breakdown  of  elastic fibers  and  loss  of  functional  elastin.  Defective or damaged elastin may lead to wrinkles, even in the absence of sun exposure and aging. A child with wrinkled skin syndrome was shown to have a deficiency of elastin fibers, which demonstrates the important contribution of elastin to skin integrity.

Studies have demonstrated that, with aging, there is a reduction in the elastin content of protected areas of the skin. In a study of Egyptian subjects, the relative amount of elastin in the non–UV-exposed abdominal skin decreased significantly from 49.2%±0.6% in the first decade of life to 30.4%±0.8% in the ninth decade. Another study on elastin content in the non–UV-exposed skin of the buttocks of 91 white subjects between 20 and 80 years of age showed a 51% reduction in elastin tissue [Baumann, Weinkle , 2007].

Glycosaminoglycans (GAGs)

Proteoglycans, a family of glycosaminoglycan (GAG) conjugated proteins, are important constituents of human skin connective tissue (dermis) and are essential for maintaining mechanical strength of the skin. Age-related alterations of dermal proteoglycans have not been fully elucidated. We quantified transcripts of 20 known interstitial proteoglycans in human skin and found that decorin was the most highly expressed. Decorin was predominantly produced by dermal fibroblasts. Decorin was localized in dermal extracellular matrix with GAG bound to type I collagen fibrils. Analysis of decorin extracted from young (21–30 years) and aged (>80 years) sun-protected human buttock skin revealed that decorin molecular size in aged skin is significantly smaller than in young skin. The average size of decorin protein did not alter, indicating size of GAG chain is reduced in aged, compared to young skin. This age-dependent alteration of decorin glycosaminoglycan may contribute to skin fragility of elderly people [Li and others, 2013].

Four different classes of sulfated glycosaminoglycans (GAGs) exist invertebrates: chondroitin sulfate (CS), dermatan sulfate (DS), keratan sulfate (KS), and heparan sulfate/heparin (HS). Hyaluronic acid is not esterified with sulfate and not linked to a protein core.

These compounds render normal skin plump, soft and hydrated, and are believed to assist in maintaining proper salt and water balance. Several studies suggest that glycosaminoglycan’s, particularly Hyaluronic acid, have been found to be reduced in amount in photo-aged skin. Some studies offer conflicting reports, however, suggesting no changes in the level of GAGs in aged skin. The fact that Hyaluronic acid is synthesized in the epidermis as well as the dermis likely accounts for this discrepancy in findings. In skin that ages intrinsically, the total HA level in the dermis remains stable; however, epidermal Hyaluronic acid diminishes almost completely [Malvi, 2011].

Hyaluronic acid:

The HA content of the dermis is far greater than that of the epidermis, and accounts for most of the 50% of total body hyaluronic acid present in skin. The papillary dermis has the more prominent levels of HA than does reticular dermis. The hyaluronic acid of the dermis is in continuity with both the lymphatic and vascular systems, which epidermal HA is not. Exogenous HA is cleared from the dermis and rapidly degraded.

The dermal fibroblast provides the synthetic machinery for dermal HA, and should be the target for pharmacological attempts to enhance skin hydration, and age- related changes. The fibroblasts of the body, the most banal of cells from a histological perpective, are probably the most diverse of all vertebrate cells with the broadest repertoire of biochemical reactions and potential pathways for differentation. Much of this diversity is site specific. What makes the papillary dermal fibroblast different from other fibroblasts is not known. However, these cells have an hyaluronic acid synthetic capacity similar to that of the fibroblast that line joint synovium, responsible for the hyaluronic acid – rich synovial; fluid. [Farage , Miller 2010]

Photoaged skin has been shown to be characterized by reduced levels of hyaluronic acid (HA) and elevated levels of chondroitin sulphate proteoglycans. Such patterns, intriguingly, are also observed in scars. Hyaluronic acid is found in young skin at the periphery of collagen and elastin fibers and where these types of fibers intersect. In aged skin, such connections with hyaluronic acid disappear. It is possible that the decreases in hyaluronic acid levels, which contribute to its disassociation with collagen and elastin as well as reduced water binding, may be involved in the changes noted in aged skin, including wrinkling, altered elasticity, reduced turgidity and diminished capacity to support the microvasculature of the skin.

As one of the primary GAGs, hyaluronic acid can bind 1000 times its weight in water, and may help the skin retain and maintain water. It is found in all connective tissue and is produced mainly by fibroblasts and keratinocytes in the skin. hyaluronic acid is localized not only in the dermis but also in the epidermal intercellular spaces, especially the middle spinous layer, but not in the stratum corneum (SC) or stratum granulosum[ Malvi, 2011].


There is a decline of 6-8% per decade after age 30, which accounts for the lighter skin color. This not only leads to a reduction in melanin (hypopigmentation), but it also accounts for a diminished protective capacity against UV exposure. Along with the decline in melanocytes, there is a reduction in both the number and functionality of the other dendritic cells of the epidermis (the Langerhans cells), which creates a lowered immune response for the skin. This results in decreased immune surveillance, which may account for the heightened incidence of premalignant and malignant lesions in aging skin [Howard D.].


Aged skin is seen to be relatively avascular. As skin ages, the vasculature progressively atrophies [Farage, Miller, 2009]. The loss of vascular network is especially notable in papillary dermis with the disappearance of the vertical capillary loops. Reduced blood flow, depleted nutrient exchange, inhibited thermoregulation, decreased skin surface temperature; skin pallor is associated with reduction in vascularity [Malvi, 2011].

In mildly photo damaged skin, the number of vascular cross- secretions is reduced and there are local dilations, corresponding to clinical telangiectases. Overall, there is a marked change in the horizontal vascularization pattern with dilated and distorted vessels [Gilchrest, Krutmann, 2006].

Subcutaneous tissue

Subcutaneos tissue loss also contributes to wrinkling. Wrinkling is particularly noticeable on the face as the skin here is constantly exposed to the atmosphere. Creases and lines particularly appear in areas of expression and use. Frown lines and crow’s feet appear on the forehead and at the corners of eyes. Loss of padding associated with reduced subcutaneous tissue, especially in the extremities, makes the arms and legs appear thinner. This loss of padding also contributes to a great risk of hypothermia, skin shearing and blunt trauma injury. Decreased basal metabolic rate and a reduced ability to regulate blood flow also contibute to the risk of hypothermia wrinkling [Farley, 2011].

Changes in Skin Appearance

Dry Skin

Dry, scaly skin is frequently seen in the elderly. The degradation or loss of skin barrier function with increasing age is partly accountable for this manifestation. The recovery of damaged barrier function has been demonstrated to be slower in aged skin, resulting in greater susceptibility to developing dryness. This is a multifactorial process due, in part, to lower lipid levels in lamellar bodies and a decrease in epidermal filaggrin. Increased trans epidermal water loss (TEWL) is also exhibited by aged skin, leaving the stratum corneum more susceptible to becoming dry in low humidity environments.

In addition to dryness, aged skin is often characterized by roughness, wrinkling, skin pallor, hyper or hypo pigmentations, laxity, fragility, easy bruising and benign neoplasms [Malvi, 2011].

The main reasons of aged skin dryness are:

  • increased compaction of stratum corneum;
  • increased thickness of granular cell layer;
  • reduced epidermal thickness;
  • reduced epidermal mucin content [Gilchrest, Krutmann,2006].

Benign Neoplasms in Aging Skin

With age, the appearance and surface texture of skin can change dramatically, as represented by the development of acrochordons (skin tags), cherry angiomas, seborrheic keratoses, lentigos (sun spots) and sebaceous hyperplasias, among other lesions and cutaneous alterations. Patients of dermatologists and plastic surgeons often request removal of these benign neoplasms. Various destructive treatment modalities are available, including hyfrecation and sundry laser options [Malvi, 2011].

Seborrheic keratoses

Seborrheic keratoses are benign epithelial neoplasms that are monoclonal in origin. They starts as flat hyperpigmented macules and progress to become hyperkeriatotic verrucous plaques highly variable in size and color. Seborrheic keratoses first appear in the third to fifth decade of life and become inceasingly numerous throughout life, independent of sun exposure. They are regarded as the best biomarker of intrinsic skin aging. Presumably they represent a focal subtle loss of homeostasis, with resulting over- proliferation of keratinocytes and melanocytes, although the pathogenesis is not known.Recently, keratinocytes with basaloid morphology in seborrheic keratoses have been reported to express high levels of endothelin- 1 (ET-1), associated with increased tyrosinase expression in the melanocytes, compared to control perielesional skin, suggesting that ET- 1- induced melanogenesis, dendricity, and melanocyte proliferation may play role in the evolution of this neoplasm.

Cherry angiomas

Cherry angiomas are small red to purple vascular malformations composed of venous capillaries and postcapillary venules that are present in the dermal papillae and are connected to each other and to the venular portion of the superfacial vascular plexus. They contain increased numbers of mast cells are known to synthesize proangiogenic factors such as vascular endothelial growth factor and basic fibroblast growth factor, they may be casually involved in the development of these age associated lesions [Gilchrest, Krutmann, 2006].



Baumann L., Weinkle S., Improving Elasticity: The Science of Aging Skin, Cosmetic Dermatology, VOL. 20 NO. 3, 2007

Chung J., Seo J., Choi H., Lee M.,  Youn Ch., Rhie G.,  Cho K., Kim K.,  Park K. and  Eun H., Modulation of Skin Collagen Metabolism in Aged and Photoaged Human Skin In Vivo, 2001

Farage M, Miller K., Maibach H., Textbook of aging Skin ,  Chapter 35, Biological effects of estrogen on skin, Zack Thompson, 2010

Farage M., Miller K., Berardesca E., Maibach H., Clinical implications of aging skin: cutaneous disorders in the elderly., Am J Clin Dermatol. 2009;10(2), Abstract

Farley A.,  McLafferty E., Hendry Ch., The Physiological Effects of Aging, John Wiley & Sons,p. 145- 146, 2011

Fratzl P., Collagen Structure and Machanics, Springer, 2008

Freedberg I.,  Eisen A., Wolff K., Austen F., Goldsmith L., Katz S., McGraw-Hill Professional, Fitzpatrick’s Dermatology In General Medicine , 6th edition , 2003

Freinkel R., Woodley T. , The Biology of the Skin, CRC Press,– 432, 2001

Fujii N.,Tajima S.,Tanaka T.,Fujimoto N., Takata T., Shimo-Oka T., The presence ofd-β-aspartic acid-containing peptides in elastic fibers of sun-damaged skin: a potent marker for ultraviolet-induced skin aging,  Biochemical and Biophysical Research Communications, Volume 294, Issue 5, 28 June 2002, Abstract

Gilchrest B., Krutmann J.,Skin Aging, Springer, 2006

Hake A., Holbrook K.., The structure and development of skin. In Freedberg, et al. ed. Fitzpatrick’s Dermathology in General Medicine, 5th edn.McGraw Hill, 1999

Histology Guide, Faculty of Biological Sciences, University of Leeds

Howard D.,Structural Changes Associated with Aging Skin, The International Dermal Institute

Li Y., Liu Y.,  Xia W.,  Lei D.,  Voorhees  J., Fisher G., Age-dependent alterations of decorin glycosaminoglycans in human skin, Scientific Reports 3, Article number: 2422, 2013

Lim H.., Honigsmann H., Hawk J., Photodermatology, CRC Press, 2013

Malvi, The Aging Skin: Structure of Skin, Cutaneous Aging and Causes of Aging, Characteristic of the Aging Skin (Part 1, 2, 3), 2011

McGrath J., Eady R., Pope  F., Rook’s Textbook of Dermatology; Chapter 3: Anatomy and Organization of Human Skin , 2008

Montagna W., Carlisle K., Structural changes in aging skin, British Journal of Dermatology, Volume 122, Issue Supplement s35,  1990, Abstract

QuanT., QinZ., XiaW., Yuan Shao,  Voorhees J., Fisher G., Matrix-Degrading Metalloproteinases in Photoaging,  Department of Dermatology, University of Michigan Medical School, 2009.

Rigel D.,  Weiss R., Lim H., Dover J., Photoaging, p.7, CRC Press,  2004

Stephens J , The Fat Controller: Adipocyte Development, Jornal Plos Biology, 2012

Wickett R., Visscher M., Structure and function of the epidermal barrier, American Journal of Infection Control, Volume 34, Issue 10, Supplement , Pages 98-110, 2006

Zappi E., Dermatopathology: Classification of Cutaneous Lesions, 2012

Zegarska B., Woźniak M., Reasons of endogenous aging of the skin,  Gerotologia Polska, tom 14, nr 4, 153–159, 2006


Leave a Comment

Your email address will not be published. Required fields are marked *