The aim of this review was to recommend training strategies that improve the functional capacity in physically frail older adults based on scientific literature, focusing specially in supervised exercise programs that improved muscle strength, fall risk, balance, and gait ability. Scielo, Science Citation Index, MEDLINE, Scopus, Sport Discus, and ScienceDirect databases were searched from 1990 to 2012. Studies must have mentioned the effects of exercise training on at least one of the following four parameters: Incidence of falls, gait, balance, and lower-body strength. Twenty studies that investigated the effects of multi-component exercise training (10), resistance training (6), endurance training (1), and balance training (3) were included in the present revision. Ten trials investigated the effects of exercise on the incidence of falls in elderly with physical frailty. Seven of them have found a fewer falls incidence after physical training when compared with the control group. Eleven trials investigated the effects of exercise intervention on the gait ability. Six of them showed enhancements in the gait ability. Ten trials investigated the effects of exercise intervention on the balance performance and seven of them demonstrated enhanced balance. Thirteen trials investigated the effects of exercise intervention on the muscle strength and nine of them showed increases in the muscle strength. The multi-component exercise intervention composed by strength, endurance and balance training seems to be the best strategy to improve rate of falls, gait ability, balance, and strength performance in physically frail older adults.
High levels of penetrating cryoprotectants (CPAs) can eliminate ice formation during cryopreservation of cells, tissues, and organs to cryogenic temperatures. But CPAs become increasingly toxic as concentration increases. Many strategies have been attempted to overcome the problem of eliminating ice while minimizing toxicity, such as attempting to optimize cooling and warming rates, or attempting to optimize time of adding individual CPAs during cooling. Because strategies currently used are not adequate, CPA toxicity remains the greatest obstacle to cryopreservation. CPA toxicity stands in the way of cryogenic cryopreservation of human organs, a procedure that has the potential to save many lives. This review attempts to describe what is known about CPA toxicity, theories of CPA toxicity, and strategies to reduce CPA toxicity. Critical analysis and suggestions are also included.
DNA methylation is a major control program that modulates gene expression in a plethora of organisms. Gene silencing through methylation occurs through the activity of DNA methyltransferases, enzymes that transfer a methyl group from S -adenosyl- l -methionine to the carbon 5 position of cytosine. DNA methylation patterns are established by the de novo DNA methyltransferases (DNMTs) DNMT3A and DNMT3B and are subsequently maintained by DNMT1. Aging and age-related diseases include defined changes in 5-methylcytosine content and are generally characterized by genome-wide hypomethylation and promoter-specific hypermethylation. These changes in the epigenetic landscape represent potential disease biomarkers and are thought to contribute to age-related pathologies, such as cancer, osteoarthritis, and neurodegeneration. Some diseases, such as a hereditary form of sensory neuropathy accompanied by dementia, are directly caused by methylomic changes. Epigenetic modifications, however, are reversible and are therefore a prime target for therapeutic intervention. Numerous drugs that specifically target DNMTs are being tested in ongoing clinical trials for a variety of cancers, and data from finished trials demonstrate that some, such as 5-azacytidine, may even be superior to standard care. DNMTs, demethylases, and associated partners are dynamically shaping the methylome and demonstrate great promise with regard to rejuvenation.
Safe and effective cell delivery remains one of the main challenges in cell-based therapy of neurodegenerative disorders. Graft survival, sufficient enrichment of therapeutic cells in the brain, and avoidance of their distribution throughout the peripheral organs are greatly influenced by the method of delivery. Here we demonstrate for the first time noninvasive intranasal (IN) delivery of mesenchymal stem cells (MSCs) to the brains of unilaterally 6-hydroxydopamine (6-OHDA)–lesioned rats. IN application (INA) of MSCs resulted in the appearance of cells in the olfactory bulb, cortex, hippocampus, striatum, cerebellum, brainstem, and spinal cord. Out of 1 × 10 6 MSCs applied intranasally, 24% survived for at least 4.5 months in the brains of 6-OHDA rats as assessed by quantification of enhanced green fluorescent protein (EGFP) DNA. Quantification of proliferating cell nuclear antigen-positive EGFP-MSCs showed that 3% of applied MSCs were proliferative 4.5 months after application. INA of MSCs increased the tyrosine hydroxylase level in the lesioned ipsilateral striatum and substantia nigra, and completely eliminated the 6-OHDA–induced increase in terminal deoxynucleotidyl transferase (TdT)-mediated 2′-deoxyuridine, 5′-triphosphate (dUTP)-biotin nick end labeling (TUNEL) staining of these areas. INA of EGFP-labeled MSCs prevented any decrease in the dopamine level in the lesioned hemisphere, whereas the lesioned side of the control animals revealed significantly lower levels of dopamine 4.5 months after 6-OHDA treatment. Behavioral analyses revealed significant and substantial improvement of motor function of the Parkinsonian forepaw to up to 68% of the normal value 40–110 days after INA of 1 × 10 6 cells. MSC-INA decreased the concentrations of inflammatory cytokines—interleukin-1 β (IL-1 β ), IL-2, -6, -12, tumor necrosis factor (TNF), interferon-γ (IFN-γ, and granulocyte-macrophage colony-stimulating factor (GM-CSF)—in the lesioned side to their levels in the intact hemisphere. IN administration provides a highly promising noninvasive alternative to the traumatic surgical procedure of transplantation and allows targeted delivery of cells to the brain with the option of chronic application.
Regular exercise has multi-system anti-aging effects. Here we summarize how exercise impacts the major hallmarks of aging. We propose that, besides searching for novel pharmaceutical targets of the aging process, more research efforts should be devoted to gaining insights into the molecular mediators of the benefits of exercise and to implement effective exercise interventions for elderly people.
A number of potential candidate genes in a variety of biological pathways have been associated with longevity in model organisms. Many of these genes have human homologs and thus have the potential to provide insights into human longevity. Recently, several studies suggested that FOXO3A functions as a key bridge for various signaling pathways that influence aging and longevity. Interestingly, Willcox and colleagues identified several variants that displayed significant genotype-gender interaction in male human longevity. In particular, a nested case-control study was performed in an ethnic Japanese population in Hawaii, and five candidate longevity genes were chosen based on links to the insulin-insulin-like growth factor-1 (IGF-1) signaling pathway. In the Willcox study, the investigated genetic variations (rs2802292, rs2764264, and rs13217795) within the FOXO3A gene were significantly associated with longevity in male centenarians. We validated the association of FOXO3A polymorphisms with extreme longevity in males from the Southern Italian Centenarian Study. Particularly, rs2802288, a proxy of rs2802292, showed the best allelic association-minor allele frequency (MAF) = 0.49; p = 0.003; odds ratio (OR) = 1.51; 95% confidence interval (CI), 1.15-1.98). Furthermore, we undertook a meta-analysis to explore the significance of rs2802292 association with longevity by combining the association results of the current study and the findings coming from the Willcox et al. investigation. Our data point to a key role of FOXO3A in human longevity and confirm the feasibility of the identification of such genes with centenarian-controls studies. Moreover, we hypothesize the susceptibility to the longevity phenotype may well be the result of complex interactions involving genes and environmental factors but also gender.
In autophagy, portions of cytoplasm are sequestered into autophagosomes and delivered to lysosomes for degradation. Long assumed to be a random process, increasing evidence suggests that autophagy of mitochondria, peroxisomes, and possibly other organelles is selective. A recent paper (Kissova et al., J. Biol. Chem. 2004;279:39068-39074) shows in yeast that a specific outer membrane protein, Uth1p, is required for efficient mitochondrial autophagy. For this selective autophagy of mitochondria, we propose the term "mitophagy" to emphasize the non-random nature of the process. Mitophagy may play a key role in retarding accumulation of somatic mutations of mtDNA with aging.
Metformin, a biguanide, is a widely used antidiabetic drug, which inhibits gluconeogenesis and is used to treat hyperglycemia in type 2 diabetes. Through activation of AMPK (AMP-activated protein kinase) pathway, metformin also mimics caloric restriction health benefits. Aging causes substantial molecular to morphological changes in brain, the brain cells being more susceptible toward oxidative stress mediated damages due to the presence of high lipid content and higher oxygen consumption. Wistar rats (naturally aged and d -galactose induced rat model) were supplemented with metformin (300 mg/kg b.w. orally) for 6 weeks. The biomarkers of oxidative stress such as antioxidant capacity (ferric reducing antioxidant potential [FRAP]), malondialdehyde (MDA), reduced glutathione (GSH), protein carbonyl (PCO), reactive oxygen species (ROS), acetylcholinesterase (AChE) activity, and nitric oxide (NO) were measured in brain tissues of control and experimental groups. The results indicate that metformin treatment augmented the levels of FRAP and GSH in naturally aged, and d -gal induced aging model groups compared to the respective controls. In contrast, metformin treated groups exhibited significant reduction in MDA, PCO, ROS, and NO levels and a significant increase in AChE activity in induced aging rats. The administration of d -galactose upregulated the expression of sirtuin-2, interleukin-6 ( IL- 6), and tumor necrosis factor-alpha ( TNF-α ) and downregulated the expression of Beclin-1. Metformin supplementation downregulated the d -galactose induced expressions of sirtuin-2, IL -6, and TNF-α expression, whereas upregulated the Beclin-1 expression. Our data confirm that metformin restores the antioxidant status and improves healthy brain aging through the activation of autophagy and reduction in inflammation.
Our objective was to construct and validate a Multidimensional Prognostic Index (MPI) for 1-year mortality from a Comprehensive Geriatric Assessment (CGA) routinely carried out in elderly patients in a geriatric acute ward. The CGA included clinical, cognitive, functional, nutritional, and social parameters and was carried out using six standardized scales and in formation on medications and social support network, for a total of 63 items in eight domains. A MPI was developed from CGA data by aggregating the total scores of the eight domains and expressing it as a score from 0 to 1. Three grades of MPI were identified: low risk, 0.0-0.33; moderate risk, 0.34-0.66; and severe risk, 0.67-1.0. Using the proportional hazard models, we studied the predictive value of the MPI for all causes of mortality over a 12-month follow-up period. MPI was then validated in a different cohort of consecutively hospitalized patients. The development cohort included 838 and the validation cohort 857 elderly hospitalized patients. Of the patients in the two cohorts, 53.3 and 54.9% were classified in the low-risk group, respectively (MPI mean value, 0.18 +/- 0.09 and 0.18 +/- 0.09); 31.2 and 30.6% in the moderaterisk group (0.48 +/- 0.09 and 0.49 +/- 0.09); 15.4 and 14.2% in the severe-risk group (0.77 +/- 0.08 and 0.75 +/- 0.07). In both cohorts, higher MPI scores were significantly associated with older age (p = 0.0001), female sex (p = 0.0001), lower educational level (p = 0.0001), and higher mortality (p = 0.0001). In both cohorts, a close agreement was found between the estimated mortality and the observed mortality after both 6 months and 1 year of follow-up. The discrimination of the MPI was also good, with a ROC area of 0.751 (95%CI, 0.70-0.80) at 6 months and 0.751 (95%CI, 0.71-0.80) at 1 year of follow-up. We conclude that this MPI, calculated from in formation collected in a standardized CGA, accurately stratifies hospitalized elderly patients into groups at varying risk of mortality.
Decline of cognition and increasing risk of neurodegenerative diseases are major problems associated with aging in humans. Of particular importance is how the brain removes potentially toxic biomolecules that accumulate with normal neuronal function. Recently, a biomolecule clearance system using convective flow between the cerebrospinal fluid (CSF) and interstitial fluid (ISF) to remove toxic metabolites in the brain was described. Xie and colleagues now report that in mice the clearance activity of this so-called “glymphatic system” is strongly stimulated by sleep and is associated with an increase in interstitial volume, possibly by shrinkage of astroglial cells. Moreover, anesthesia and attenuation of adrenergic signaling can activate the glymphatic system to clear potentially toxic proteins known to contribute to the pathology of Alzheimer disease (AD) such as beta-amyloid (Abeta). Clearance during sleep is as much as two-fold faster than during waking hours. These results support a new hypothesis to answer the age-old question of why sleep is necessary. Glymphatic dysfunction may pay a hitherto unsuspected role in the pathogenesis of neurodegenerative diseases as well as maintenance of cognition. Furthermore, clinical studies suggest that quality and duration of sleep may be predictive of the onset of AD, and that quality sleep may significantly reduce the risk of AD for apolipoprotein E (ApoE) ɛ4 carriers, who have significantly greater chances of developing AD. Further characterization of the glymphatic system in humans may lead to new therapies and methods of prevention of neurodegenerative diseases. A public health initiative to ensure adequate sleep among middle-aged and older people may prove useful in preventing AD, especially in apolipoprotein E (ApoE) ɛ4 carriers.
Bone marrow (BM)-derived mesenchymal stem cells (MSCs) represent a promising population for supporting new concepts in cellular therapy. This study was undertaken to assess the efficacy and feasibility of autologous BM-derived MSCs in the treatment of chronic nonhealing ulcers (diabetic foot ulcers and Buerger disease) of the lower extremities. A total of 24 patients with nonhealing ulcers of the lower limb were enrolled and randomized into implant and control groups. In the implant group, the patients received autologous cultured BM-derived MSCs along with standard wound dressing; the control group received only the standard wound dressing regimen, followed up for at least a 12-week period. Wound size, pain-free walking distance, and biochemical parameters were measured before therapy and at every 2-week interval following intervention. The implant group had significant improvement in pain-free walking distance and reduction in ulcer size as compared to those in the control group. In the implant group for Buerger disease, the ulcer area decreased from 5.04 +/- 0.70 cm(2) to 1.48 +/- 0.56 cm(2) (p < 0.001), whereas the pain-free walking distance increased from 38.33 +/- 17.68 m to 284.44 +/- 212.12 m (p < 0.001). In the diabetic foot ulcer group, the ulcer size decreased from 7.26 +/- 1.41 cm(2) to 2 +/- 0.98 cm(2) (p < 0.001) at 12 weeks. Mononuclear cells were cultured for a minimum of five passages and characterized by cell-surface markers showing CD90(+), CD105(+), and CD34(-). There was no significant alteration in the biochemical parameters observed during the follow-up period, indicating normal liver and renal function following intervention. Biopsy microsection of implanted tissues showed development of dermal cells (mainly fibroblasts), including mature and immature inflammatory cells. The study indicates that autologous implantation of BM-derived MSCs in nonhealing ulcers accelerates the healing process and improves clinical parameters significantly.
Oxidative stress and decreased DNA damage repair in vertebrates increase with age also due to lowered cellular NAD+. NAD+ depletion may play a major role in the aging process at the cellular level by limiting (1) energy production, (2) DNA repair, and (3) genomic signaling. In this study, we hypothesize that it is not NAD+ as a cofactor in redox reactions and coenzyme in metabolic processes that has the ultimate role in aging, but rather the role of NAD+ in cellular signaling when used as substrate for sirtuins (SIRT1-7 in mammals) and PARPs [Poly(ADP-ribose) polymerases]. Both sirtuins and PARPs influence many transcription factors and can affect gene expression. As a signaling molecule, NAD+ is consumed in the reaction donating ADP-ribose and releasing nicotinamide (NAM) as a by-product. It seems that aging at the cellular level is associated with a decline of NAD+ and that NAD+ restoration can reverse phenotypes of aging by inducing cellular repair and stress resistance. Adequate intracellular NAD+ concentrations may be an important longevity assurance factor, while lowered cellular NAD+ concentration may negatively influence the life span.
Advancing age is the focus of recent studies on familial and sporadic Alzheimer's disease (AD), suggesting a prolonged pre-clinical phase several decades before the onset of dementia symptoms. Influencing some age-related conditions, such as frailty, may have an impact on the prevention of late-life cognitive disorders. Frailty reflects a nonspecific state of vulnerability and a multi-system physiological change with increased risk for adverse health outcomes in older age. In this systematic review, frailty indexes based on a deficit accumulation model were associated with late life cognitive impairment and decline, incident dementia, and AD. Physical frailty constructs were associated with late-life cognitive impairment and decline, incident AD and mild cognitive impairment, vascular dementia, non-AD dementias, and AD pathology in older persons with and without dementia, thus also proposing cognitive frailty as a new clinical condition with co-existing physical frailty and cognitive impairment in non-demented older subjects. Considering both physical frailty and cognitive impairment as a single complex phenotype may be central in the prevention of dementia and its subtypes with secondary preventive trials on cognitive frail older subjects. The mechanisms underlying the cognitive–frailty link are multi-factorial, and vascular, inflammatory, nutritional, and metabolic influences may be of major relevance. There is a critical need for randomized controlled trials of intervention investigating the role of nutrition and/or physical exercise on cognitive frail subjects with the progression to dementia as primary outcome. These preventive trials and larger longitudinal population-based studies targeting cognitive outcomes could be useful in further understanding the cognitive–frailty interplay in older age.
This review synthesizes behavioral research with neuromolecular mechanisms putatively involved with the low-toxicity cognitive enhancing action of Bacopa monnieri (BM), a medicinal Ayurvedic herb. BM is traditionally used for various ailments, but is best known as a neural tonic and memory enhancer. Numerous animal and in vitro studies have been conducted, with many evidencing potential medicinal properties. Several randomized, double-blind, placebo-controlled trials have substantiated BM's nootropic utility in humans. There is also evidence for potential attenuation of dementia, Parkinson's disease, and epilepsy. Current evidence suggests BM acts via the following mechanisms—anti-oxidant neuroprotection (via redox and enzyme induction), acetylcholinesterase inhibition and/or choline acetyltransferase activation, β-amyloid reduction, increased cerebral blood flow, and neurotransmitter modulation (acetylcholine [ACh], 5-hydroxytryptamine [5-HT], dopamine [DA]). BM appears to exhibit low toxicity in model organisms and humans; however, long-term studies of toxicity in humans have yet to be conducted. This review will integrate molecular neuroscience with behavioral research.
Reducing sugars can react non-enzymatically with the amino groups of proteins, lipids, and nucleic acids to initiate a complex series of rearrangements and dehydrations, and then to produce a class of irreversibly cross-linked heterogeneous fluorescent moieties, termed advanced glycation end products (AGEs). The formation and accumulation of AGEs in numerous tissues have been known to progress in a normal aging process and at an accelerated rate under hyperglycemic and/or oxidative stress conditions. There is a growing body of evidence that interaction of AGEs with a cell-surface receptor termed receptor for AGEs (RAGE) elicits oxidative stress generation and subsequently evokes proliferative, angiogenic, and inflammatory reactions, thereby being involved in the development and progression of various types of cancers. These observations suggest that accumulation of AGEs and resultant activation of the RAGE signaling pathway could partly explain the increased risk of a variety of cancers in patients with diabetes or in elderly subjects. This article summarizes the pathological role of RAGE activation by AGEs and other ligands in tumor growth and metastasis and its therapeutic interventions for the life-threatening disorders.
Age-related skeletal muscle sarcopenia is linked with increases in falls, fractures, and death and therefore has important socioeconomic consequences. The molecular mechanisms controlling age-related muscle loss in humans are not well understood, but are likely to involve multiple signaling pathways. This study investigated the regulation of several genes and proteins involved in the activation of key signaling pathways promoting muscle hypertrophy, including GH/STAT5, IGF-1/Akt/GSK-30/4E-BP1, and muscle atrophy, including TNF alpha/ SOCS-3 and Akt/FKHR/atrogene, in muscle biopsies from 13 young (20 +/- 0.2 years) and 16 older (70 +/- 0.3 years) males. In the older males compared to the young subjects, muscle fiber cross-sectional area was reduced by 40-45% in the type 11 muscle fibers. TNF alpha and SOCS-3 A were increased by 2.8 and 1.5 fold, respectively. Growth hormone receptor protein (GHR) and IGF-1 mRNA were decreased by 45%. Total Akt, but not phosphorylated Akt, was increased by 2.5 fold, which corresponded to a 30% reduction in the efficiency of Akt phosphorylation in the older subjects. Phosphorylated and total GSK-3/3 were increased by 1.5 and 1.8 fold, respectively, while 4E-BP1 levels were not changed. Nuclear FKHR and FKHRL1 were de creased by 73 and 50%, respectively, with no changes in their atrophy target genes, atrogin-1 and MuRF1. Myostatin mRNA and protein levels were significantly elevated by 2 and 1.4 fold. Human sarcopenia may be linked to a reduction in the activity or sensitivity of anabolic signaling proteins such as GHR, IGF-1, and Akt. TNF alpha, SOCS-3, and myostatin are potential candidates influencing this anabolic perturbation.
Background Curcumin, an extract from the rhizome of the plant Curcuma longa (turmeric), has been widely used as a spice and herbal medicine m Asia It has been suggested to have many biological activities, such as antioxidative, antiinflammatory, anticancer, chemopreventive, and antineurodegenerative properties We evaluated the impact of curcumin on life span, fecundity, feeding rate, oxidative stress, locomotion, and gene expression in two different wild-type Drosophila melanogaster strains, Canton-S and Ives, under two different experimental conditions Results We report that curcumin extended the life span of two different strains of D melanogaster, an effect that was accompanied by protection against oxidative stress, improvement in locomotion, and chemopreventive effects Life span extension was gender and genotype specific Curcumin also modulated the expression of several aging-related genes, including mth, thor, InR, and JNK Conclusions The observed positive effects of curcumin on life span and health span in two different D melanogaster strains demonstrate a potential applicability of curcumin treatment in mammals The ability of curcumin to mitigate the expression levels of age-associated genes in young flies suggests that the action of curcumin on these genes is a cause, rather than an effect, of its life span extending effects
A decline in physical and/or cognitive function is a common feature of aging, and frailty has been shown to be associated with cognitive impairment and dementia. This study aimed to evaluate the association between dynapenia, sarcopenia, and cognitive impairment among community-dwelling older people in Taiwan. Data from the I-Lan Longitudinal Aging Study (ILAS) were retrieved for study. Global cognitive function was assessed by Mini-Mental State Examination (MMSE), whereas the Chinese Version Verbal Learning Test, Boston Naming Test, Verbal Fluency Test, Taylor Complex Figure Test, Digits Backward Test, and Clock Drawing Test were used to assess different domains of cognitive function. Association between sarcopenia and global cognitive function as well as all different dimensions of cognitive function were evaluated. Data from 731 elderly participants (mean age 73.4 ± 5.4 years, 53.8% males) were used for study analysis. The overall prevalence of sarcopenia was 6.8%, which was significantly higher in men (9.3% versus 4.1%, p < 0.05). The mean MMSE score was 23.4 ± 4.4 for all participants, and 10.3% of the study participants were cognitively impaired. Sarcopenia was not significantly associated with global cognitive function (odds ratio [OR] = 1.55, p = 0.317), but global cognitive impairment was significantly associated with low physical performance (OR = 2.31, p = 0.003) and low muscle strength (OR = 2.59, p = 0.011). Nonetheless, sarcopenia was significantly associated with impairment in the verbal fluency test (OR = 3.96, p = 0.006) after adjustment for potential confounders. Dynapenia was significantly associated with cognitive impairment in multiple dimensions and global cognitive function, but sarcopenia was only associated with an impaired verbal fluency test. Reduced muscle strength and/or physical performance related to non-muscle etiology were strongly associated with cognitive impairment. More longitudinal studies are needed.
Cognitive decline and dementia represent very important public health problems that impact the ability to maintain social function and independent living. The aim of this study was to investigate the effects of a nonpharmacological intervention consisting of comprehensive cognitive training in elderly people having one of three different cognitive statuses. In all, 321 elderly people with a diagnoses of mild–moderate Alzheimer's disease (AD), with mild cognitive impairment (MCI) and without cognitive decline were randomly assigned to two groups: experimental group (EG, who underwent intervention) and control group (CG), according to a prospective randomized intervention study. In the three groups, immediately after the end of the intervention, we observed a significant effect on some cognitive and noncognitive outcomes in the EGs. At the end of the intervention, we found an intermediate intervention effect on the Alzheimer's Disease Assessment Scale (ADAS) score of subjects with AD, as well as on functional status, as measured by using the Instrumental Activities of Daily Living scale. A significant intervention effect was also observed on enhancement of auditory verbal short-term memory and subjective memory complaints of subjects with MCI. The group of subjects without cognitive decline obtained a significant intervention effect on subjective complaints outcomes. The obtained results demonstrated that participation in the intervention could improve performance with respect to specific cognitive functions and psychological statuses. The role of healthy lifestyle programs, such as the use of comprehensive interventions, has been shown to be efficient for enhancing memory and other abilities in aged individuals with and without cognitive decline.
Heparan sulfate (HS), due to its presence on the cell surface and in the extracellular milieu and its ability to modulate cell signaling, has a fundamental role in both physiological and pathological conditions. For decades we have demonstrated the occurrence of interactions between glycosaminoglycans (GAGs) and elastic fibers. In particular, we have recently shown that HS is present inside elastic fibers and plays a role in the assembly and stability of elastin coacervates. Elastin represents, within the extracellular matrix, the component most severely affected during aging, and changes in the synthesis and posttranslational modifications of HS have been described, possibly influencing cellular behavior and protein interactions. Thus, the present study has investigated, in two different in vitro experimental models, the role of HS on elastin deposition and assembly. Results demonstrate that: (1) Biological effects of HS are partly dependent on the physicochemical characteristics of the GAGs; (2) HS does not affect attachment, viability, and growth of human dermal fibroblasts; (3) HS does not modify elastin gene expression nor elastin synthesis, but favors α-elastin aggregation and, independently from the age of donors, elastin assembly; (4) HS significantly increases the expression of fibulin 5, and these effects are especially evident in fibroblasts isolated from aging donors. These data provide a better understanding of the biological role of HS and offer new perspectives regarding the possibility of restoring and/or preserving the elastic component with aging.