 ageing  is one of the most complex biological processes of growing older and defined as the intrinsic , inevitable , and irreversible age - related process of loss of viability and increase in vulnerability or a progressive functional decline , or a gradual deterioration of physiological function with age , including a decrease in fecundity .
some workers refer to it as  senescence .  recently , ageing is defined as the age - dependant fractal process consisting in increasing of quantity of homeostasis disturbances at molecular , subcellular , cell - tissue , and system levels .
the life cycle of human cells are determined by strings of dna called telomeres , present at the ends of chromosomes .
the telomere shortens each time a cell divides , leading to ageing and eventually the death of the cell , once the telomere becomes too short to sustain life .
genes regulate the ageing speed by indirection and controlling organism resistance to damages by exogenous and endogenous stresses .
silencing of genomic dna was first observed by repression of genes near certain translocation breakpoints in drosophila .
factors , such as proteins encoded by the sirtuin genes , have been identified in drosophila and yeast that act in trans to mediate silencing .
sirtuins ( sir , silent information regulator ) are a group of  nad - dependent deacetylases ,  hypothesized to play a key role in an organism 's response to stresses ( such as heat or starvation ) and to be responsible for the lifespan - extending effects of calorie restriction and/or a mutation in one or two genes , such as , ras2 and sch9 .
sir2 is required for silencing in the rdna , but sir2 , sir3 , and sir4 are all required for silencing at mating - type loci and telomeres .
limited overexpression of the sir2 has been observed to result in a lifespan extension of about 30% and the deletion of sir2 results in a 50% reduction in lifespan .
the sir2 homolog in mammals is known as sirt1 or sir2. it has been proposed that sir2 and sirt1 may block the organism from entering an extreme survival mode characterized by the absence of reproduction , improved dna repair , and increased protection against cell damage .
mice that overexpress sirt1 show properties of calorie restriction , including low cholesterol , low blood glucose , and low insulin levels and also show increased numbers of mitochondria in their neurons .
the human sirt1 protein has been demonstrated to deacetylate several downstream effector proteins including ku70 , nbs1 , the foxo transcription factor family , and p53 , several of which are in response to dna damage events occurring within the cell .
sirt1 may also stimulate autophagy by preventing acetylation of proteins required for autophagy in cultured cells and embryonic and neonatal tissues which shows a link between sirtuin expression and the cellular response to limited nutrients due to caloric restriction .
nicotinamide riboside , a new nadprecursor , regulates sir2 deacetylase activity and life span in yeast and the ability of nicotinamide riboside to enhance lifespan does not depend on calorie restriction .
it has been observed that the dual specificity tyrosine phosphorylation - regulated kinase 1a ( dyrk1a ) and 3 ( dyrk3 ) promote cell survival through phosphorylation and activation of sirt1 and single copy loss - of - function of dyrk1a leads to increased apoptosis .
klotho gene(named after a greek goddess who spins life 's thread ) to high blood pressure .
boosting the activity of the klotho gene appears to extend the natural lives of male mice as well as it also seems to delay many of the effects of old age , like the weakening of bones , clogging of the arteries , and loss of muscle fitness . increased p53 activity has also been implicated in ageing .
it has been revealed that tap63 ( a p53 family member ) is a critical gene in preventing organismal ageing by controlling the maintenance of dermal and epidermal precursor and stem cells .
gene expression is imperfectly controlled , and it is possible that random fluctuations in the expression levels of many genes contribute to the ageing process .
individual cells , which are genetically identical but can have substantially different responses to outside stimuli , and markedly different life spans , indicate that the epigenetic factors also play a role in gene expression and ageing .
increasing evidences have shown that autophagy , a highly conserved lysosome - mediated catabolic process , plays important roles in maintenance of energy homeostasis and the quality control of proteins and small organelles .
autophagy is involved in a number of pathophysiologies , including ageing and age - related diseases ; however , its roles in these processes are far from straightforward .
it was shown that this  replicative exhaustion  is essentially telomere shortening , which activates a persistent dna damage response .
based on the intensity of the stress and acuteness of the process , rs and oncogene - induced senescence ( ois ) may reflect natural ageing and age - related disease , respectively .
autophagy in lower eukaryotes has been shown to be critical for the anti - ageing effects of dietary restriction and negative modulation of insulin - signaling . in rs
, there is a gradual shift from the proteasome pathway to autophagy within polyubiquitinated protein degradation systems which is mediated through at least two members of the bag ( bcl-2-associated athanogene ) protein family , which can bind to chaperones of the hsc / hsp70 family and thereby modulate protein quality control .
the increase of bag3/bag1 ratio and activation of autophagy is also found in tissue ageing ; however , autophagy capacity declines with age in vivo .
interleukin 6 ( il6 ) and interleukin 8 ( il8 ) have recently been shown to reinforce the senescence phenotype .
the timing of their induction has been correlated with autophagy activation during the transition phase .
strikingly , rnai - mediated repression of atg5 or atg7 , which are essential genes for autophagy , suppresses il6/8 production , indicating a functional relevance of autophagy in senescence .
components of the pi3k pathway , including mtor , a negative regulator of autophagy , are attenuated after their acute activation following ras expression during the transition phase of ois .
cellular energy generation in the mitochondria is both a key source and key target of oxidative stress in the cell .
cytochrome c oxidase , nadh dehydrogenase , and succinate dehydrogenase that regulate both oxidation and cellular respiration in mitochondria are believed to play a role in age - related increases in oxidation .
an increased production of free radicals has been proposed to compromise mitochondrial efficiency , and eventually energy output , in a detrimental feedback loop .
these energy - deficient cells lack the minimum metabolic capacity necessary to carry out an orchestrated cell - removal program known as  apoptosis . 
another pathway to ageing involves the accumulation of proteins with toxic carbonyl groups in cells .
carbonylation results from protein oxidation and reactions of proteins with sugars , aldehydes , and lipid peroxidation products .
protein carbonylation increases with age , damaging about one - third of the body 's proteins later in life .
these dysfunctional proteins accumulate in vital organs including the skin and eye , clogging the cellular machinery . with growing age ,
our neuroendocrine and immune systems decline functionally and this may cause these systems to send inflammatory chemical signals contributing to cell senescence or cell death .
also , with growing age , there is a decline in the levels of essential polypeptide hormone insulin - like growth factor 1 ( igf-1 , somatomedin c ) .
igf-1 coordinates cellular function and regulate cell growth and division and is responsible for many of the age - defying effects attributed to hgh .
igf-1 plays an important role in preventing apoptosis in the early development of the embryo , as well as in the progressive regulation of organ development .
igf-1 research shows that igf-1 can reverse many of the physical signs of ageing , such as loss of muscle strength , mass , and endurance , sagging skin , wrinkles , etc .
shortages or imbalances of igf-1 are now thought to be a key factor in the ageing process and also in the development of ageing - related health disorders such as alzheimer 's disease , diabetes , and atherosclerosis .
a recent study suggested that higher growth hormone / igf-1 levels in adulthood play a determinant role not only for regressive manifestations , but also for longer lifespan .
marked changes in the expression levels of the neurotrophin receptors , trka and p75 , occur with ageing of the brain as trka expression predominates in younger animals which switches to p75 predominating in older animals . the igf-1 receptor ( igf1-r ) , the common regulator of lifespan and age - related events in many different organisms , has been shown responsible for the trka - to - p75 switch in both human neuroblastoma cell lines and primary neurons from mouse brain .
the signaling pathway that controls the level of trka and p75 downstream of the igf1-r requires irs2 , pip3/akt , and is under the control of pten and p44 , the short isoform of p53 .
the hyperactivation of igf1-r signaling in p44 transgenic animals , which show an accelerated form of ageing , is characterized by early trka - to - p75 switch and increased production of a in the brain .
recently , scientists have shown that yeast cells age through succeeding cell divisions and chromosomal instability dramatically increases when a threshold is crossed , thereby increasing genetic defects and age - related degeneration .
telomeres are also considered important indicators of cellular senescence and vascular ageing and found to be shortened in senescent cells as a consequence of the increased production of mitochondrial reactive oxygen species ( ros ) .
the phosphorylation of the telomerase reverse transcriptase ( tert ) by tyrosine kinase src results into its export from the nucleus .
the ageing - induced lack of nuclear tert activity finally leads to cellular senescence due to telomere shortening and consequent chromosome instability .
p66shc protein has been investigated extensively as part of a critical pathway for loss of endothelial integrity associated with ageing and ros generation .
a recent report has proposed that mediators other than p66shc , like o2- , are actively involved in determining the injurious effects of both ageing and hypertension .
mutations causing a reduction in protein kinase a signaling have been shown to extend lifespan in yeast .
it also delayed the incidence and severity of age - related disease and promoted leanness and longevity in mice .
persons who are genetically predisposed to produce high levels of il-6 have a reduced capacity to reach the extreme limits of human life , whereas the high il-10-producer genotype is increased among centenarians .
recently , two genes for which rnai knockdown delayed age - associated locomotory decline , conferring a high performance in advanced age phenotype ( hpa ) , hpa-1 and hpa-2 , have been identified as novel negative regulators of egf signaling , and egf signaling has been revealed as a major pathway for healthy ageing , acting through downstream phospholipase c - gammaplc-3 and inositol-3-phosphate receptor itr-1 .
inflammaging , an increased inflammation state with ageing , has been proposed mainly on the basis of peripheral levels of inflammatory cytokines and acute phase reaction proteins .
it is linked to immunosenescence , an age - related decline in the functionality of the immune system .
although the signaling pathways and mechanisms whereby inflammation inhibits muscle protein synthesis are not fully understood , chronic inflammation is an important player in sarcopenia and muscle weakness .
adipocytes from old c57bl mice have significantly higher mrna expression of the proinflammatory cytokines il-1 , il-6 , tnf- , and lipid inflammatory mediator cox-2 and lower expression of anti - inflammatory nuclear receptor ppar- than those of young mice .
an age - associated upregulation in nuclear factor ( nf)-b binding activity has been shown to be present in various types of mouse tissues , and this elevated nf-b activity was diminished by a ppar agonist , suggesting that activation of nf-b in adipocytes is upregulated with ageing , resulting in increased expression of its target genes and , consequently , secretion of their products . highly significant differences between cytokine generation by t cells and monocytes of old and young subjects with gender specificity has also been observed .
patients with mutations in the nalp3 gene secrete more il-1 and il-18 and suffer from systemic inflammatory diseases .
they also have high circulating levels of il-6 and c - reactive protein ( crp ) which decrease rapidly upon blockade of the il-1 receptor , suggesting that il-1 contributes to the elevation of these markers of the inflammatory mechanisms of ageing . in a recent study of sfas , which is a known inhibitor of apoptosis , sfasl ,
a known stimulator of apoptosis , and total cytochrome c , which is released from cells during apoptosis , serum levels of sfas were significantly higher while sfasl and cytochrome c levels were lower in men compared with women . with increasing age , there was a decrease in apoptotic markers ( cytochrome c ) and pro - apoptotic factors ( sfasl ) and an increase in anti - apoptotic factors ( sfas ) in circulation .
this shift toward less global apoptosis with increasing age in normal subjects is consistent with increased incidence of diseases whose pathophysiology involves apoptosis dysregulation .
the understanding of pathophysiology of ageing over the past few years has posed tremendous challenges for the development of anti - ageing medicine for targeted therapy . in order to extend lifespan
, an anti - ageing drug must delay ageing process or at least age - related diseases .
inhibition of the signal transduction pathway for il6-mediated inflammation is suggested as the key to the prevention and treatment of ageing and age - related disorders , which may be achieved either indirectly through regulation of endogenous cholesterol synthesis and isoprenoid depletion or by direct inhibition of the il-6 signal transduction pathway .
statins and bisphosphonates inhibit the mevalonate to cholesterol conversion pathway and cause isoprenoid depletion with inhibition of il-6 inflammation .
statins inhibit the enzyme hmg - coa reductase and bisphosphonates inhibit the enzyme fpp synthase .
polyphenolic compounds inhibit multiple pathways of signal transduction for il-6-mediated inflammation including inhibition of tyrosine kinase activity , inhibition of activation of nf-b , and inhibition of activation of ikk complex .
statins , bisphosphonates , and polyphenolic compounds inhibit the jak / stat3 signaling pathway for il-6-mediated inflammation .
resveratrol and rapamycin target conserved longevity pathways and may mimic some aspects of dietary restriction . they have also been reported to slow ageing in yeast and invertebrate species .
in addition , both compounds also show beneficiary effects in rodent models of age - associated diseases .
these compounds hold great promise as therapies to target multiple age - related diseases by modulating the molecular causes of ageing .
resveratrol also increases the activity of sir2 , which is the postulated reason for its beneficial effects , although with debated validity .
free radical damage causes cellular energy depletion and further generation of more toxic free radicals .
these cells may not go through normal apoptosis , produce inflammatory cytokines further damaging healthy cells , and also become chromosomally instable .
antioxidant drugs could protect against the ageing effects of free radicals and slow down ageing considerably .
plant sterols ( ps ) and stanols consumption is known to decrease low - density lipoprotein cholesterol ( ldl - c ) levels .
furthermore , ps have recently been investigated for the prevention of other age - related diseases .
ps may also have other potential beneficial effects including anti - inflammatory , antioxidant and anti - cancer activities .
zingerone , found in ginger root , has been shown to have antioxidative and anti - inflammatory activities .
zingerone has not only the antioxidant effect by constitutive suppression of ros , but also anti - inflammatory effects by suppression of nf - kappab activation in aged rat .
in addition , zingerone treatment suppresses gene activation of proinflammatory enzymes , cox-2 and inos , which were upregulated with ageing through nf - kappab activation and ikk / mapk signaling pathway .
experiments strongly indicate that zingerone treatment exerts a beneficial efficacy by suppressing both oxidative stress and age - related inflammation through the modulation of several key proinflammatory genes and transcription factors .
madeo et al . , hypothesized that increased autophagic turnover of cytoplasmic organelles or long - lived proteins is involved in most if not all lifespan - prolonging therapies .
exogenous supply of spermidine , a polyamine , prolongs the lifespan of several model organisms and significantly reduces age - related oxidative protein damage in mice .
spermidine induces autophagy in cultured yeast , nematodes , and flies as well as in mammalian cells .
. many therapists also believe that the human growth hormones , melatonin and testosterone , can also prevent ageing .
dehydroepiandrosterone ( dhea ) and its sulfate dheas are the most abundant sex steroids in women , the levels of which decline with age .
it has been proposed that restoring the circulating levels of these steroids to those found in young women may have anti - ageing effects and improve sexual function and wellbeing in postmenopausal women .
it is postulated that morin 's anti - nf - kappab activation depends on its ability to scavenge excessive reactive species ( rs ) .
anthocyanidins and related compounds extracted from the fruits and seeds of shrubs belonging to genus vaccinium have been reported to possess antioxidant and anti - inflammatory properties .
extracts of the fruits have been applied for the inhibition of nonenzymatic glycosylation in anti - ageing preparations .
histometric evaluations have shown that the dimethylaminoethanol ( dmae)-supplemented anti - ageing formulation led to increased dermal thickness and also increase in collagen fiber thickness .
dmae also enhanced the stratum corneum water content in the forearm skin without significantly modifying the mechanical properties .
peptides , such as palmitoyl - kttks pentapeptide , applied topically in moisturizer - type cosmetic products are known to improve the appearance of fine lines , wrinkles , and other signs of facial skin ageing .
a dipeptide , pal - kt , increases expression of skin structural biomarkers in human skin equivalents .
gene microarray analysis indicated that pal - kt does not affect just the dermis and basement membrane in vitro , but can also affect biomarkers associated with epidermal differentiation , wound healing , and longevity , and has anti - ageing effects on skin .
n - acetyl glucosamine ( nag ) , a precursor to hyaluronic acid , serves important structural and hydration roles in extracellular matrix in both the epidermis and the dermis , and improves the appearance of uneven coloration and hyperpigmented spots in ageing facial skin .
human skin equivalent cultures treated topically with nag show a dose - dependent increase in hyaluronic acid in parallel with an increase in procollagen-1 expression .
a number of molecular mechanisms that cause ageing and ageing - associated disease have been identified and found to have interconnected pathways . to date , most studies have focused on interconnectedness of inflammation and its mediators and age or age - related diseases .
future research areas must include targeted role of systemic inflammatory markers such as crp and il-6 and other biochemical and genetic studies including gene signaling pathways , gene microarray analysis , gene modulation , gene therapy , and development of animal / human models for potential therapeutic measures and evaluations .
 ageing , also called as senescence , is one of the most complex , intrinsic , biological processes of growing older and resulting into reduced functional ability of the organism . 
 telomerase , environment , low calorie diets , free radicals , etc . 
 , are all believed to affect this ageing process . 
 a number of genetic components of ageing have been identified using model organisms . 
 genes , mainly the sirtuins , regulate the ageing speed by indirection and controlling organism resistance to damages by exogenous and endogenous stresses . in higher organisms , ageing is likely to be regulated , in part , through the insulin / insulin - like growth factor 1 pathway . 
 besides this , the induction of apoptosis in stem and progenitor cells , increased p53 activity , and autophagy is also thought to trigger premature organismal ageing . 
 ageing has also been shown to upregulate expression of inflammatory mediators in mouse adipose tissue . 
 the understanding of pathophysiology of ageing over the past few years has posed tremendous challenges for the development of anti - ageing medicine for targeted therapy . 
 future research areas must include targeted role of systemic inflammatory markers such as c - reactive protein and interleukin 6 and other biochemical and genetic studies including gene signaling pathways , gene microarray analysis , gene modulation , gene therapy , and development of animal / human models for potential therapeutic measures and evaluations . 
Introduction
Gene Regulation
Quality and Quantity Control of Proteins in Senescence
Pathways of Ageing
Immune System Dysfunction, Inflammaging, and Apoptosis in Senescence
Antiageing Therapy
Future Research