|
Modulation of skin collagen metabolism in aged and photoaged
human skin in vivo.
To the best of our knowledge, no study has been conducted to date to directly
compare the collagen metabolism of photoaged and naturally aged human skin. In
this study, we compared collagen synthesis, matrix metalloproteinase-1 levels,
and gelatinase activity of sun-exposed and sun-protected skin of both young and
old subjects. Using northern blot analysis, immunohistochemical stain, and Western
blot analysis, we demonstrated that the levels of procollagen type I mRNA and
protein in photoaged and naturally aged human skin in vivo are significantly
lower than those of young skin. Furthermore, we demonstrated, by northern blot
analysis, that the procollagen alpha1(I) mRNA expression of photoaged skin is
much greater than that of sun-protected skin in the same individual. In situ
hybridization and immunohistochemical stain were used to show that the expression
of type I procollagen mRNA and protein in the fibroblasts of photoaged skin is
greater than for naturally aged skin. In addition, it was found, by Western blot
analysis using protein extracted from the dermal tissues, that the level of procollagen
type I protein in photoaged skin is lower than that of naturally aged skin. The
level of matrix metalloproteinase-1 protein and the activity of matrix metalloproteinase-2
were higher in the dermis of photoaged skin than in naturally aged skin. Our
results suggest that the natural aging process decreases collagen synthesis and
increases the expression of matrix metalloproteinases, whereas photoaging results
in an increase of collagen synthesis and greater matrix metalloproteinase expression
in human skin in vivo. Thus, the balance between collagen synthesis and degradation
leading to collagen deficiency is different in photoaged and naturally aged skin.
J Invest Dermatol. 2001 Nov;117(5):1218-24
Mathematical models describing polymer dissolution: consequences
for drug delivery.
Polymer dissolution is an important phenomenon in polymer science and engineering
that has found applications in areas like microlithography, controlled drug
delivery, and plastics recycling. This review focuses on the modeling efforts
to understand the physics of the drug release process from dissolving polymers.
A brief review of the experimentally observed dissolution behavior is presented,
thus motivating the modeling of the mechanism of dissolution. The main modeling
contributions have been classified into two broad approaches - phenomenological
models and Fickian equations, and anomalous transport models and scaling law-based
approaches. The underlying principles and the important features of each approach
are discussed. Details of the important models and their corresponding predictions
are provided. Experimental results seem to be qualitatively consistent with
the present picture.
Adv Drug Deliv Rev . 2001 Jun 11;48(2-3):195-210
Enhanced skin permeation of a lipophilic drug using supersaturated
formulations.
Supersaturation was used to enhance the permeation of a lipophilic model compound
(a lavendustin derivative, LAP) through excised pig skin in vitro. The drug
was dissolved in a series of liquid and semisolid vehicles (in which it had
different solubilities) and which were prepared using either (i) the method
of mixed cosolvents, (ii) the method of solvent evaporation, or (iii) the method
of dissolving the drug with heating. Saturated formulations showed comparable
permeation rates through the skin, independent of the absolute concentration
of the drug in the vehicle. Supersaturated solutions at a degree of saturation
of two resulted in a doubling of the drug permeation rate. These experiments
show, therefore, that the percutaneous absorption of LAP may be consistently
increased using supersaturated formulations, independent of the type and composition
of the vehicles and independent of their method of preparation.
J Control Release. 2001 Jun 15;73(2-3):245-53
Image analysis of dermal collagen changes during skin aging.
OBJECTIVE: To determine progressive quantitative, directional and textural
changes in dermal collagen as a function of age and sex and to estimate their
evolutive trend with appropriate regression models. STUDY DESIGN: Ninety-six
samples of abdominal skin from autopsy cases were analyzed. The ages ranged
from 3.5 months to 86 years. Picro-Sirius-stained slides were examined by polarizing
microscopy, and spatial density, directional features and texture of collagen
were measured by computerized image analysis. Nonlinear regression models were
built to estimate evolutive changes with respect to age. The relationship between
spatial orientation of collagen bundles and age was best modeled by linear
regression. RESULTS: The evolutive patterns of dermal thickness and spatial
density of collagen bundles correspond to a second-order polynomial model with
a progressive increase from childhood to middle age and a relatively sharp
decrease after the seventh decade. The evolution of textural pattern of dermal
collagen, defined by gradient analysis, depicts a sort of inverted U. Its complexity
is maximum in the first year of life, decreases until the period 25-50 years
and increases progressively after the sixth decade. The horizontal orientation
of collagen bundles with intermingled fascicles oriented in other directions,
shown by young individuals, is progressively simplified with aging. In elderly
subjects, collagen bundles have a horizontal orientation. No significant sex-related
differences were found. CONCLUSION: Dermal collagen changes related to aging
are apparently independent of sex, at least in abdominal skin, and show characteristic
curvilinear evolutive trends defined by decreased dermal thickness in the elderly,
decrease in the spatial density of collagen bundles and increase in textural
heterogeneity of the dermis. Progressive simplification in the orientation
of collagen bundles leading to a predominant horizontal disposition followed
a linear trend. These changes could contribute to providing a substantial morphologic
basis to age-associated biomechanical alterations in the skin.
Anal Quant Cytol Histol . 1998 Dec;20(6):493-9
Aging of the extracellular matrix and its pathology.
Recent concepts on the mechanisms of aging of extracellular matrix (EM) are
reviewed as well as its involvement in age-associated diseases. Cell differentiation,
histogenesis and organogenesis can be analyzed in terms of the program of the
biosynthesis of EM macromolecules during development, maturation and aging.
The most important biological role of EM is the integration of cells in tissues,
of tissues in organs and of organs in the whole organism. EM can directly influence
cell behavior through the contact between EM and the genome mediated by structural
glycoproteins (fibronectin, laminin, elastonectin, etc.) interacting with other
EM macromolecules (collagen, proteoglycans, elastin) and the cytoskeleton by
trans-membrane receptors (integrins). Most age-associated diseases exhibit
a deviation (qualitative or quantitative) from the normal program of EM biosynthesis.
Three examples are analyzed in some detail: atherosclerosis, diabetes and malignant
tumors. The degradation of elastic fibers catalyzed by cellular elastase-type
enzymes is observed in atherosclerosis and also in emphysema and skin aging.
Several of these enzymes were isolated and characterized from platelets, fibroblasts,
smooth muscle cells and lipoproteins. The biosynthesis of some of them increases
with age and facilitates cell migration. Plasma fibronectin increases with
age exponentially. This increase is absent or strongly attenuated in diabetes
and some cancers. Tissue fibronectin increases in diabetes, Werner syndrome
and in the peritumoral desmoplastic reaction while most tumor cells can no
more retain fibronectin on their membrane facilitating their movement in the
organism. These examples demonstrate the importance of the study of cell matrix
interactions for gerontology.
Exp Gerontol. 1988;23(1):5-18
Fifty years of skin aging.
In developed countries, interest in cutaneous aging is in large part the result
of a progressive, dramatic rise over the past century in the absolute number
and the proportion of the population who are elderly (Smith et al, 2001). The
psychosocial as well as physiologic effects of skin aging on older individuals
have created a demand for better understanding of the process and particularly
for effective interventions. Skin aging is a complex process determined by
the genetic endowment of the individual as well as by environmental factors.
The appearance of old skin and the clinical consequences of skin aging have
been well known for centuries, but only in the past 50 y have mechanisms and
mediators been systematically pursued. Still, within this relatively short
time there has been tremendous progress, a progress greatly enhanced by basic
gerontologic research employing immunologic, biochemical, and particularly
molecular biologic approaches.
J Investig Dermatol Symp Proc . 2002 Dec;7(1):51-8
Physiological consequences of human skin aging.
The expression and treatment of cutaneous disease in the elderly differ from
those applicable to younger adults. Anatomical changes in aging skin result
in altered physiological behavior and susceptibility to disease. Decreased
epidermal renewal and tissue repair accompany the aging process. The rate of
hair and nail growth declines, as well as the quantity of eccrine, apocrine,
and sebum secretion. There are alterations in immune surveillance and antigen
presentation with aging. The cutaneous vascular supply is decreased, leading
to decreases in inflammatory response, absorption, and cutaneous clearance.
Impaired thermal regulation, tactile sensitivity, and pain perception occur
as one ages. We summarize the major changes that occur during the intrinsic
aging process of the skin to facilitate the recognition and treatment of skin
disease in the older patient.
Cutis. 1989 May;43(5):431-6
Histologic changes in skin associated with aging.
This is a review of histologic changes noted in the skin of elderly
individuals. Among the epidermal changes associated with skin aging
are a flattened dermal-epidermal junction, giving the appearance of
atrophy and cellular heterogeneity. The melanocyte density declines
slowly, and the Langerhans cells decrease in number with advancing age.
Among the dermal changes are attenuation in the number and diameter
of elastic fibers in the papillary dermis, an increase in number and
thickness of the same fibers in the reticular dermis, and a coarsening
of collagen fibers with an increase in density of the collagen network.
A decrease in the dermal cell population as well as a functional decline
in glandular activity are also noted with intrinsic aging. A decline
in hair number, rate of growth, and diameter, along with a slowing of
the rate of growth of nails, have been well documented with progressive
aging.
J Dermatol Surg Oncol . 1990 Oct;16(10):908-14
Aging and cross-linking of skin collagen.
This report represents a clear demonstration of a cross-link in collagen whose
abundance is related to chronological aging of an organism. Recently its structure
was identified as histidinohydroxylysinonorleucine. Quantification of the cross-link
in various aged samples of bovine and human skin indicate that it rapidly increases
from birth through maturation. Subsequently, a steady increase occurs with
aging, approaching 1 mole/mole of collagen. This compound seems to be related
to the relative proportions of soluble to insoluble collagen from skin in neutral
salt, dilute acid, and denaturing aqueous solvents (higher concentration in
the insoluble portion). It is absent from other major collagenous tissues such
as dentin, bone and tendon.
Biochem Biophys Res Commun . 1988 Apr 29;152(2):898-903
Connective tissue biochemistry of the aging dermis. Age-associated
alterations in collagen and elastin.
Cutaneous aging represents a complex situation in which at least two independent
factors--innate aging and solar exposure--contribute to the development of
degenerative changes in the dermis. The biochemical and ultrastructural evidence
reviewed in this article indicates that reduced collagen deposition, as a result
of diminished collagen biosynthesis and reduced proliferative capacity of the
fibroblasts, could explain the development of dermal atrophy and would relate
to poor wound healing in the elderly. At the same time, perturbations in the
supramolecular organization of the elastic fiber network lead to alterations
in the mechanical properties of the skin, as manifested by loose and sagging
skin with reduced resilience and elasticity.
Clin Geriatr Med . 1989 Feb;5(1):127-47
Factors of skin ageing share common mechanisms.
Ageing has been defined as the accumulation of molecular modifications which
manifest as macroscopic clinical changes. Human skin, unique among mammalians
insofar as it is deprived of fur, is particularly sensitive to environmental
stress. Major environmental factors have been recognized to induce modifications
of the morphological and biophysical properties of the skin. Metabolites from
ingested or inhaled substances do affect skin, which is also sensitive to endogenous
hormone levels. Factors as diverse as ultraviolet radiation, atmospheric pollution,
wounds, infections, traumatisms, anoxya, cigarette smoke, and hormonal status
have a role in increasing the rate of accumulation of molecular modifications
and have thus been termed 'factors of ageing'. All these factors share as a
common feature, the capability to directly or indirectly induce one of the
steps of the micro-inflammatory cycle, which includes the expression of ICAM-1
in endothelial cells. This triggers a process leading to the accumulation of
damages in the skin resulting in skin ageing since ICAM-1 expression provokes
recruitment and diapedesis of circulating immune cells, which digest the extracellular
matrix (ECM) by secreting collagenases, myeloperoxidases and reactive oxygen
species. The activation of these lytic processes provokes random damage to
resident cells, which in turn secrete prostaglandines and leukotrienes. These
signaling molecules induce the degranulation of resident mast cells which release
the autacoid histamine and the cytokine TNF-alpha thus activating endothelial
cells lining adjacent capillaries which release P-selectin and synthesize ICAM-1.
This closes a self-maintained micro-inflammatory cycle, which results in the
accumulation of ECM damage, i.e. skin aging. In this paper we review the evidence
that two factors able to induce macroscopical and molecular modifications in
the skin, protein glycation and stretch, activate the micro-inflammatory cycle.
We further present evidence that three additional factors, two external factors
(electromagnetic fields and psychological stressors) and one internal factor
(neuropeptides) also activate the micro-inflammatory cycles and may therefore
be considered as factors of skin ageing.
Biogerontology. 2001;2(4):219-29 |