during the past decade , the field of stem cell biology has developed considerably following reports demonstrating that adult stem cells possess great abilities in tissue regeneration and regenerative medicine . many efforts have been focused on understanding the molecular mechanisms that regulate their plasticity in order to exploit this capacity for a therapeutic use . stem cells are classified as embryonic stem cells ( es cells ) , adult stem cells , and induced pluripotent stem cells ( ips cells ) . stem cells can be defined as ( i ) undifferentiated ( lacking a tissue - specific differentiation marker ) , ( ii ) capable of proliferation , ( iii ) self - renewable , ( iv ) able to produce a large number of differentiated functional progeny and ( v ) able to regenerate tissue after injury . a large number of studies suggested that stem cells from one tissue can cross lineage and differentiate into cells of other lineages either in vitro or in vivo after transplantation . recent studies support the hypothesis that stem cells in several tissues are largely retained in a quiescent state but can be induced to re - enter into the cell cycle in response to extracellular cues , injuries or diseases , even after a long period of dormancy . in order to promote regeneration or repair processes , the stem cells reactivate their proliferative cycle through signal stimulations , while the somatic cells remain inactive . this concept suggests that stem cells are capable of self - regulating the cells cycle . however , it is still unclear whether the stem cells are influenced by extracellular signals from a  niche  , or their stimulation is dependent by the aging process . the plasticity , or ability of stem cells to trans - differentiate , has been a source of great interest for its therapeutic potential in tissue engineering , in particular in peripheral nerve regeneration . adipose tissue has been shown to contain adult mesenchymal stem cells ( msc ) that have therapeutic applications in regenerative medicine . in previous studies , the use of msc isolated from bone marrow ( bm - msc ) , or adipose - derived stem cells ( asc ) have demonstrated successful differentiation towards the schwann cell - like ( sc ) lineage following the exposure to the mitogen glial growth factor ( ggf ) , and incubation of the cultures with -mercaptoethanol and all - trans - retinoic acid . however , it is becoming increasingly clear that their therapeutic potential may be limited by senescence , or by the age of the donor . aging is a complex process in which gradual deterioration of physiological function involves virtually all cells and tissues in an organism . this functional decline is associated with a diminished capacity to maintain normal tissue homeostasis and by a reduced regenerative capacity of tissues in old organisms in response to injury . for instance , bharali and lisney ( 1990 ) showed that in rats of 4 to 40 weeks of age , the nerve regeneration potential was weakly affected by the age at which injury occurred , whereas the rats injured at 2 weeks of age showed significantly reduced peripheral nerve regeneration . changes in the peripheral neural pathway are most likely caused by modifications in the extracellular matrix . demonstrated that the amount of laminin present in intact nerves from aged rats was significantly less than that from young adults rats . it is also known that during aging , there is a reduction in the level of peripherin , which is involved in axonal growth . it is clear that a comprehensive understanding of the importance of age - related differences in nerve regeneration capacity , as well as of the effects of modulatory factors , is essential for the development of tissue engineering solutions . studies on stem cell senescence started almost half a century ago , when the first report describing the limited replicative potential of primary cells in culture has been published . mammalian aging has been defined as a reduction in the capacity to maintain adequate tissue homeostasis or to repair tissue after an injury . tissue homeostasis and regenerative capacity are nowadays considered to be related to the stem cell pool present in every tissue . for this reason , when an organism undergoes unfavourable physiopathological conditions the reduction in stem cells number and/or function may develop . however , the correlation between organism aging and cell senescence remains controversial despite decades of studies . it is to be considered that the cell type , the nature and the magnitude of the damage or stress might be responsible for the switch between the biological processes of senescence and apoptosis . in order to evaluate the relationship between physiological process of aging and the biological mechanisms regulating senescent cells , different intracellular factors have been proposed to influence the cell cycle in tissue from organism of different ages . it should be highlighted that any of these factors may be exclusive of the senescent state , whereas all of them require an adequate time to exert their action . during the last few years researchers have investigated the pathways involved in telomeric shortening , as well as the regulation of some important intracellular proteins like p38 mitogen activated protein kinase ( p38 mapk ) , p53 mapk ( also known as protein 53 or tumor protein 53 ) and other senescence factors . also , dna damage and oxidative stress may account for an age - related decline in cellular proliferation . it has also to be considered that asc produce various growth factors supporting peripheral nerve regeneration [ e.g. , ggf , brain derived neurotrophic factor ( bdnf ) , nerve growth factor ( ngf ) ] , whose secretion seems to be maintained regardless of donor age . the first process is strictly related to telomere dysfunction , the second is the result of different mechanisms like mitochondrial damage , activated oncogenes and epigenetic changes . telomeres are defined as the end part of eukaryotic chromosomes , and consist of nucleotide repeats that are shortened after each replication cycle . telomerase is a nuclear enzyme deputed to elongate and protect telomeres , and the telomerase that no longer accomplish an end - protective function is defined as dysfunctional . therefore , the reduced length of telomeres is indicative of the proliferative stage of the cells , hence the measure of telomere length and telomerase activity provides an early marker for cellular senescence . however , no studies have been reported yet on the possible relationship between telomerase activity and asc damaged by stress or isolated from elderly donor . therefore , it would be interesting to investigate whether this type of dna damage influences the biological features of asc isolated from individual of different ages in relation to their possible therapeutical application . it is strongly activated by stress , playing an important role also in immune response , and in the regulation of cell survival , differentiation and apoptosis induction . p38 mapk , also known as rk , csbp and sapk2a , was initially described as a 38-kda protein mediating the inflammatory response of several cytokines . overall , the role of p38 mapk signalling in cellular responses is complex , depending upon stimulus and cell types . the stress activated p38 mapk may contribute to cellular senescence by up - regulating p16 , possibly through an indirect mechanism . additionally , a role for p38 mapk in aging process has been implied in several cell types , including haematopoietic stem cells , msc as well as epithelial stem / progenitor cells . indeed , the regulation of proliferation , survival and differentiation of normal haematopoietic stem cells by different cytokines and growth factors occurs via p38 mapk signalling . it should be highlighted that among stem cell regulators , wnt and notch refer to intracellular signalling which are not completely elucidated . conversely , p38 mapk , which lie downstream to those regulators , is able to promote adult neural differentiation by activating transcription factors such as transforming growth factor- ( tgf- ) . through this pathway p38 mapk that asc / bm - msc are important for nerve regeneration , the attention has been focused on the role of p38 mapk in undifferentiated ( uasc and ubm - msc ) and differentiated types ( dasc and dbm - msc ) of mesenchymal stem cells . in uasc isolated from animals of different ages ( neonatal , young and old ) , p38 mapk was present in all the groups of cells analyzed and its expression was increased with the aging of rats . this result strengthens the hypothesis that the cellular senescence may be linked to the age of the donor . interestingly , in the neonatal dasc there are significant differences in p38 expression levels when compared to cells from young / old rats , but the difference is not significant when compared cells from the young to the old rat groups . it was suggested that the last absence of effect may result from the compensatory action of fibroblast growth factor type 2 ( fgf2 ) and platelet - derived growth factor ( pdgf ) , which were used for feeding and stem cells differentiation in culture . in conclusion , the mechanisms at the base of p38 mapk regulation of cellular senescence is likely to be complex and it is still an open to debate . for example , it has been recently shown that p38 mapk inhibits sirtuin-1 , whose involvement in aging process is becoming increasingly important . many studies have demonstrated that senescence and apoptosis share the signalling pathway p53 mapk as a common regulator . it plays an important role in activating genes that arrest cell proliferation , or it facilitates those genes that are involved in apoptosis . as with p38 mapk , p53 mapk is also activated by various stimuli , such as stress , dna damage or inappropriate expression of oncogenes , which can lead to tumorigenesis and cell apoptosis . p53 mapk activation may also depend on other factors , such as the cell type , the different p53 mapk post - translational modifications or the recruitment of different co - factors . there are emerging data indicating that p53 mapk and nf - b signalling are linked to each other , and this relationship is important in the regulation of cellular senescence and aging process . p53 mapk is normally expressed at low levels in the cells due to the action of an ubiquitin ligase called mdm2 , which promotes p53 mapk degradation . when the binding between p53 mapk and mdm2 is disrupted by adverse stimuli , the accumulation of p53 mapk in the nucleus modifies the expression of genes inducing either apoptosis or cell cycle arrest for these reasons , p53 mapk is so - called  guardian of the genome  or a key regulator of cell death  . in line with this correlation , the deactivation of the mammalian target of rapamycin ( mtor ) prevented senescence , causing cellular quiescence . different studies have shown that there is a cross - talk between p53 mapk and mtor signalling pathways . nevertheless , blagosklonny and colleagues noted that p53 mapk induction does not always lead to cellular senescence , thus questioning the role of p53 mapk in the senescence . indeed , this study indicates that p53 mapk suppresses senescence and promotes cellular quiescence , in a way that the cells remain in a state of transient cell arrest induction . in vivo experiments have shown that p53 mapk is involved in cell differentiation as well as in cell - fate decisions that occur during development of the nervous system . a few studies have shown that p53 mapk reaches a maximum level of mrna expression during embryonic development of several tissues , including early neuronal precursor cells in the mouse brain . since the efficiency of p53 mapk - mediated responses to cellular stresses was shown to be decreased during aging , it has been hypothesized that p53 mapk signalling lessenes the aging process of an organism . in line with this hypothesis , and considering the involvement of p53 mapk in msc , we expected that in neonatal , young and old umsc , the expression of p53 mapk changes with aging . despite a slight increase of p53 mapk expression was observed in dasc and dmsc , its expression in the undifferentiated cells does not change . based on this concept , we suggested that possible mutations of p53 mapk are implicated in age - related msc transformation , either in the self - renewal and differentiation of msc . hence , the pharmacological modulation of p53 mapk signalling may represent a target and a challenge for the application of asc and msc in nerve regenerative medicine , although this would require further investigations . mitochondria are central organelles of the cells that during normal activity supply energy in the form of atp . therefore , the number of mitochondria in a cell is determined by the specific cell function and by its energy needs . cells such as highly metabolic heart muscle cells have numerous mitochondria , whereas red blood cells have none . mitochondria are also involved in the process of cell death and apoptosis . in a model of mitochondrial participation to apoptosis , bcl-2 family members ( bax and bak ) have been shown to control this process by regulating mitochondrial morphogenetic pathways . based on the correlation between aging and apoptosis , mitochondria may assume an important role in development of aging . in addition to the their traditionally described anabolic / catabolic roles , mitochondria appear to regulate a variety of cellular processes , such as cell proliferation and aging in many cell types . generally , aging is characterized both by an impairment of the mitochondrial respiratory function and by an increased production of ros , leading to a cumulative oxidative damage which may affect either the mitochondrion or other intracellular components . according to the literature , many researchers are supporting the concept that intact mitochondrial function is crucial for the maintenance of stem cell pluripotency and renewal . in particular , it has been suggested a strict correlation between dna damage , p53 mapk activation and mitochondrial dysfunction . above all , p53 mapk activation would impair mitochondrial function either directly and indirectly , increasing ros levels and leading to dna damage ( figure 1 ) . schematic representation of the most important intracellular signalling pathways which correlate cellular senescence , cell death and apoptosis to environmental stimuli . these mechanisms may be potentially relevant for the biology of adipose - derived stem cells and for their application in regenerative medicine . p38 mapk : protein 38 mitogen activated protein kinase ; ros : reactive oxygen species ; bcl2 : b - cell lymphoma 2 . in asc from old animals , most mitochondria were clustered around the nucleus , while in the neonatal animals mitochondria are homogenously distributed along the cells . the aggregation of mitochondria in the perinuclear region of post - mitotic cells , observed in apoptosis and in necrosis may be due to a variety of reasons . as a consequence of these structural changes , the diminished expression of the respiratory chain complex results in a reduction of membrane potential . moreover , the reduced mitochondrial fusion and their perinuclear clustering , observed in old animals , might indicate a decreased energy production in aging cells . interestingly , a study performed in primate adult asc reported that low - passage cell cultures , containing a high proportion of undifferentiated stem cells , show significant perinuclear clustering of mitochondria when compared to late - passage cells . additionally , a study conducted on embryonic stem cell undergoing differentiation has shown high level of mitochondrial activity , which may be due to mitochondrial dna replication . we can speculate that the degree of mitochondrial activity in adult stem cells may also be strongly dependent upon the target lineages into which these cells differentiate . altogether , the differences observed among these studies may be ascribed to the age of the donor tissues from which the stem cells were derived . in agreement with this hypothesis , our preliminary data suggested a correlation between mitochondrial functions and age - related origin of asc / msc . sirtuins are important molecules correlated to the aging process , as well as to metabolism , stress tolerance , apoptosis and inflammation in several organisms . in mammalian cells , sirtuins are a group of nad - deacetylases - dependent proteins that have been defined as sirtuin 1 , 2 , 3 , 6 , and possibly 5 and 7 . sirtuins regulate the circadian clocks and the mitochondrial biogenesis , as well as controlling the cell energy efficiency and alertness during low - calorie situations . moreover , it has been demonstrated that sirtuins can influence adipocyte , myocyte and neuronal differentiation through the activation of different signalling pathways such as p53 mapk , peroxisome proliferator - activated receptor gamma coactivator 1-alpha ( pgc-1 ) and nf-b , . notably , sirtuin1 can decrease p53 mapk activity , or stimulate mitochondrial biogenesis through pgc-1 activation . although this molecular mechanism correlating p53 and mitochondrial dysfunction is supported by in vitro and in vivo studies , some aspects remain to be elucidated . also , the inhibitory effect of p38 mapk on sirtuin 1 in regulating cellular senescence needs further investigation . recently , it has been reported that sirtuins induce a neuroprotective effect in acute and chronic neurological diseases . unfortunately , there are no recent studies reporting the role of sirtuins in peripheral nerve regeneration . the changes in stem cell functions , related to aging can be attributed to a decline in the effectiveness of regenerative capability and to environmental cues . this determines a lack of response of stem cells to extrinsic signals , so that they are unable to participate in the tissue repair processes . in this review , we presented some of the most important intracellular signalling pathways that challenge and regulate cellular senescence . many studies have addressed questions relating to stem cell rejuvenation and their protection from insults , although other studies showed that age does not affect the ability of asc to support regeneration following an injury . altogether these data emphasize the complexity and controversy of the mechanisms regulating stem cell senescence . given that asc are important for peripheral nervous system regeneration , the study of all the factors described in this reviews is of particular relevance and fundamental for setting the protocols to apply for stem cells therapy .
adult mesenchymal stem cells , specifically adipose - derived stem cells have self - renewal and multiple differentiation potentials and have shown to be the ideal candidate for therapeutic applications in regenerative medicine , particularly in peripheral nerve regeneration . 
 adipose - derived stem cells are easily harvested , although they may show the effects of aging , hence their potential in nerve repair may be limited by cellular senescence or donor age . 
 cellular senescence is a complex process whereby stem cells grow old as consequence of intrinsic events ( e.g. , dna damage ) or environmental cues ( e.g. , stressful stimuli or diseases ) , which determine a permanent growth arrest . 
 several mechanisms are implicated in stem cell senescence , although no one is exclusive of the others . in this review 
 we report some of the most important factors modulating the senescence process , which can influence adipose - derived stem cell morphology and function , and compromise their clinical application for peripheral nerve regenerative cell therapy .