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- - - - They subjected young mice and age mice to a haemorrhagic shock injury(HII) causes a significant amount of blood loss leading to inadequate blood flow to the body's tissues and organs and found that the young mice survided for a more extended period, compared to others ( in the absence of fluid resuscitiation) the result suggested a survival advantage for the young mice possibly indicating a maturation dependent decline in the abilty to survive the following acute injury. based on this and previous studies of HP they hypothesised that blood of young mice might have molecular signature of their resilience to HI
        
        They looked at Extracellular vesicels enriced plasma from the young mice and adminsinstered to the old mice follwoing HI, results showed a longer survival duration. the mice also showed better mitchondrial function, indicating improved cellular energetics in the old recipients. (EVs are released from cells that contain protiens,lipids, nucleic acids and are present in all blody fluids
        
        there studeis demostrated an antioxidant effect for Y-EVs but the specific factors imparting the effect in the Y-Es remains unkown. the maturational dependence of these factors that differentiate Y-EVs from EVs iolated from older ages also needs to be establised. One study demostrated that EVs from young animals improved age bioenergetics annd skeletal muslce regeneration. futhermore it is known that exsomal-Nerf2 can modulate oxidative stress and induce tissue repair and regeneration
        
        Emerging experimental evidence suggests that ageing is associated with a decrease in pro-youthful factors and an increase in oro-ageing factors (pap 8) the mechanisms underlying the rejuvenation effects of soluble factors in the young blood are mainly unknown. moreover the question of whether these factors share molecular identity and mechanistic processes of juvenile protective factors and their relationship to organsimal maturation, organ cross-talk and ageing
        
        Systemic inflammation and enhanced oxidatve stress are characteritisc of HI. Y-EVs treatment= reudced inflam. and alleviated oxidated stress in old mice.
        
        The activty of Nrf2 a mastor regulator in antioxidant response regulation was sig, enahced in the liver following Y-Evs treatment the transcription factor Nrf2 is cruciial in antioxidant resposnes and redox homeostatis. Nrf2 modulates the expression of hundreds of genes (regulating antioxidants, cytoprotection, anti-inflammatory process, tissues remodelling and carcinogenesisNrf2 signalling plays an essential role in geulating the cellular reposne in association with several other signalling pathways that control fundamental cellular porecess e.g apoptosis, proliferation, migration and angiogenesis.
      - LINK ABOUT SYSTEMIC FACTORS
  - - - ageing a complex process involoving transcriptomic changes associated with deterioration across multiple tissues and organs, including the brain. they performed single-cell transcriptomic profiling of young and oly mouse brains after parabiosis to better understand the aspects of age-associated decline and how they are modifiable or reversible.for each cell type they cateolged alternations in gene expression molecular pathways, transcriptional networks, ligand-receptor intercation and senesence status,
        
        they identified gene signaturrs, demostrating that HP regulates sveral hallmerks of ageing in a cell type-specifc manner. Brain Endothelial cells were especially malleable to this intervention, they exhibtied dynamic transcriptional changes that affect vascular structure and function.
        
        the findings suggest new strategies for slowing deterioration and driving regeneration in the ageing brain through approaches that do not only rely on disease-specific mechanisms or actions of individuals circulating factors.
      - Background and k the brain is affected substantially by ageing in such processes as: cellular respiration, protien syntheses, oxidative stress etc. nurogenesis infammation and blood flow are comprised,.
        
        Previous publications have concluded that the exposure of old mice to the young Circulatory environment mporves the function of various tissues and organs. and other studies from the auothers have shown that CF(circulating factors) in young blood stimulate functional imrovement in aged and diseased brains. Conversly it t has been shown that systemic factors in old blood drive aging phenotypes in young tissues. Alot of work has been focuses on measuring age related changes in serum blood proteins, based on the hypotheses that function improving factors decline with age, this is a plausable approach, it ignores non protein factors (Blood cells, exosomes, lipids) and factors that do or do not change in unexpected dirction wtih ageing.
        
        they used single cell RNA-Sequecning to describe changes occring in the brain during ageing, and quantifed those changes in the transcriptomes of young and old mouse brains after parabiosis. they were able to dectect brain cell types, the transcriptonal states of which are affected by parabiosies. they also idenifted changes in inter/intracellular molecular pathways, gene regulatory networks, cell-cell intercations and senesence. Endotheial cells were highly affected by parabiosis they exhibted strong dynmaic changes in thier transcriptome. this work shows that HP regulates several canonical hallmarks of ageing, by shifting ageing induced changes of the transcriptomes in a cell- type-specific manner
    - - Parabioses reprograms the transcriptoinal landscape of brain cell types
        
        They performed Differential gen expression (DGE) analysis to identify the gene changes that are associated with the rejuvenation process in old heterchronic parabionts or with the acceleration process in young H parabionts. They used HP as a first pass filter to help identify those ageing-related genes that drive the reveals of ageing in the brain.
        
        The data allowed us to idenifty signatures that either shifted more toward reveral (RJV) or accelerated ageing (AGA). the RJV DGE dataset lists of the old Heterchronic genes are associated with a transistion to a more youthful stste with repsct to normal ageing. ( the phenotype has been changed) the ageing AGA DGE dataset lists the young heterchronic genese are assocaited wit ha transition to a more aged state.
        
        of the 20,905 total detected genes, 700 were sig. changed with ageing in at least one cell types. 442 were sig. changed in RJV and 155 in AGA. They didnt capture significant transcriptional changes in the idenifed cell types( this could be due to the low number of cells sequenced in some populations and the low levles of detection transcription etc)
        
        The analysis showed that the proportions of total DGEs per cluster that were common to ageing and RJV and ageing and AGC varied from cell type to cell type. the DGes in common between each paradigm along with genes unique to each paradigm demonstrate that not all affects of ageing are reversed or accelerate by P. and that HP may also work though genes and pathways independent of the ageing process
        
        Examining DGE data sets: a clear pattern of gene expression changes in RJV and AGA was evident among large cell populations . along with other cells (see paper) ECs, yielded the largest number of putative DGEs (are genes that are suspected to be differentially expressed between different conditions, but their status hasn't been fully confirmed yet) ECs, an average cluster in size had the 3rd highest % of AGA and DGEs. this data indicates that the EC population, most directly exposed to circulating factors is highly affected in both the RJV and the AGA paradigms this is in accordance with our previous observation showing improvements in the brain vasculature after HP and after GDF11 treatment. thus further emphasizes the key role that ECs play in regulating communications between the blood and the brain.
      - Parabiosis shifts gene signatures associated with RJV and AGA
- - - - The Mexican axolotl, retain striking regenerative capacity throughout their lives. the development of age-related disease is rare in this organisms. aims is how we can apply the lessons we learn from studying regeneration in the axolotl to understand and potentially treat, age related decline in humans
    - - Regenerative capacity declines with age in humans can be linked to a decreased intrinsic responsiveness of the stem cells or decrease environmental signals, e.g. that from the niche have be documented in multiple somatic stem cell populations. also decreased ability to self-renew and altered potential to diferetiate into progenitor populations is observed in ageing somatic stem cells. leading to a decreased ability to replace or repair damaged or senescent cells that have a negative effect on the tissue envrionment.
        
        Regenerative decline may be due to changes in fibroblast activtiy. fibroblasts are present in every organ system, and are rich in connective tissues. Fibroblats have a recognised role in their ability to generate extracellular matrix molecules that consitues as the glue that hold tissues and organs together. They are known to retian postional memory e.g. they remeber where they are located realtive to the different axes of the body and even within a particular structure. most other cell types (termed pattern following cells) in the body do not retain this memory. instead they repond to posistion-specific cues from fibroblasts. these cues regulate gene expression in the pattern-following cells(explore microenvironments) (paper7) Fibroblats appear essential for tissues homeostatis in every major organ system. The altered activty of fibroblasts during ageing can have a negative impact on the overall helath in humans. Aberrat fibrotic activty is responsible for scarring in reposne to acute injury. some of the major age-related chronic dieases inclduing heart dieases etc involve tissue firbrosis.
        
        Ageing in axolotl
        
        Fibroblasts play multiple essential roles in wound healing and regeneration in the axolotl, thus the axolotl is an excellent model to study the regulation of fibroblast activty during regenerative responses in adult
        
        the maximum life expectancy of an axolotle is estimated to be up to 25 years in captivty. behaviour changes are seen with age, and young axos exhibit more frequent locomotion and feeding compared to older animlas suggesting that metabolsim also decreases with age. Precise comparison between ageing in humans and the axos cannot be conducted due to the limited data relating to the aging in the axolotl. But axos can be looked at their resistance to age related disease and pathologies, it has been hypothesized that this resistance is due to in part their expectional regenerative capctiy.
        
        the aplical epithlial cap( signalling feedback loops between the nerve and the wound epithelium which establishes a specialezed signalling center) the centre generates multiple signalling molecules that result in dedifferentiation and prolifeation of the underlying mature limb tissues into lim progenitor cells. interactions in the wound between cells from opposite axes of the limb established the pattern of the missing limn structres (paper 19) once pattern is established, the cell re-differentiate into missing limb structures. (paper 20)
        
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        Decline in ageing the age related decline in regernative ability in the axolotl could be due to numerous factors. with age the skin of the axolotle thickens ans losses dlexibilty, making it more difficult to form a wound epithelium as well as increase the likehood of generating insufficent positional interactions for the genetation of a complete limb structure as the site of injury. additional factors such as circulatory factors and hormones could aslo play a role in the timining of regeneration in ageing animlas although this possiblity has not been investigated uet
        
        dimished sensory and motor function is a hallmark of ageing process in humans and nerve signalling is required for axoltl limb regernation and wound healing. if nerve signalling is removed from an amputated limb stump it will form scar tisues and fail to regneration (papaer 29,30) it has been establsiehd that a threshold number of nerves must be present at the wound surfacr for limb regenration to process(pap 31) the current research has been to identify neurotropic factors that are required for regeneration. using ALM assay fibroblast growth factors and bone morehpgenetic proteins( specfic protiens that can subsitue for nerve signalling and induce ectopic limb function )
    - - the immune system
      - Scar free healing
      - low incidence of cancer
      - HP and tissues grafting
        
        HP faciltates improves muslce and liver regenerative capacity in old mice. demostrated by imporved activation of resident-age progenitor muslce and hepatic cells respectivtly,. when paired with young mice, they ym exhbit slightly reduced progenitor cell activation in this experiment(pap67) the findings indicate that age-related systemic factors have a greater capacity to alter regenerative success than the autonomous capacity of progenitor cells themselves for contrivery see (pap 68_
        
        Experiments with muscle tissues have been done in murine models and demostrated age related effects, old muscle exhibited improved regen. abilityes when implanted into a young murine host while young graft was impaired in the old recipient mice. The findings indicate that systemic factors have a stronger effect, relative to autonomous factors, in regulating muslce regenerative capcaity (pap73)
        
        it would be intersing to determinif similar effects would be exhibited in a highly regenrative species such as the axoltl, muslce satllite cells are known to particpate in limb regeneration (74) and hence the capctiy of these progenitor cells in differently aged axolotl hots may provide insights regarding their autonomous regerative ability and the effects of systemic factors with age.
    - - Couplying micro-arry and RNA-sequenceing techologies with the now availavle genomic sequence of the axolotl will facilitate a far more complete understanding of gene expression during regeneration