Senescence in MPB

[chore boy]

Came across this kinda on accident when researching telomeres. Kudos to Kingpin on introducing me to senescence.


Previous studies have reported that DPC from balding scalp grow slower in vitro than DPC from non-balding scalp (Randall et al., 1996). In this study, we were able to confirm the slow growing nature of balding DPC in comparison to non-balding cells. However, we show that this loss of proliferative capacity as demonstrated by both cell proliferation assay and decreased PCNA expression is associated with the onset of premature senescence as characterized by the appearance of flat, enlarged and vacuolated cells, SA--Gal staining, and increased_expression of p16INK4a and pRb (Bayreuther et al., 1988; Alaluf et al., 2000; Chen et al., 2004).

A number of physiological stimuli can induce cell senescence. These include extensive passage in culture commonly referred to as replicative senescence (Hayflick and Moorhead, 1961), exposure to environmental stress (Chen et al., 1995; von Zglinicki et al., 1995), and oncogene activation (Serrano et al., 1997; de Stanchina et al., 1998). Replicative senescence following extensive passage in culture is usually associated with progressive telomere shortening and involves the activation of p53 and p21Cip1 (Dulic et al., 2000; Itahana et al., 2001). Whereas senescence induced by environmental stress is mediated via the p16INK4a/Rb pathway (Jacobs and de Lange, 2004). Our data showing that senescence of balding DPC is associated with increased expression of p16INK4a and pRb and not p53 suggests that the senescence of balding DPC in vitro is stimulated by environmental stress and is not due to replicative senescence. It is known that the rapid onset of senescence in some cell types may be caused by the stress of cell culture including high oxygen tension, lack of interactions with neighboring cells, growth on plastic as well as growth factor, and nutrient deficiencies of tissue culture medium (Sherr and DePinho, 2000; Ben-Porath and Weinberg, 2005). In our study, only balding DPC showed this premature stress response with non-balding DPC undergoing repeated passage in vitro. This suggests that balding DPC are more susceptible to the stress of tissue culture than non-balding cells. That balding DPC may be more susceptible to stress in general was further highlighted by our observation that when matched cultures of balding and non-balding DPC from the same patients and same passage (P2) were stored in liquid nitrogen; non-balding DPC could be routinely recovered back into culture, whereas balding DPC could not be retrieved (unpublished observation). In total, we have cultured balding DPC from over 20 patients and all have been slow to grow in culture and shown premature senescence. In contrast, we have never seen this in a similar number of non-balding DPC cultures. Furthermore, we routinely culture DPC from female facelift skin, pubic and hirsute biopsies as well as male beard and have not seen premature senescence in any of these cultures. Although we cannot completely exclude the possibility that this premature senescence is a site-specific phenomenon of frontal scalp follicles, we suggest this is unlikely for the reasons outlined above. It has not been possible to obtain frontal scalp biopsies from healthy male patients, although we have obtained non-balding male scalp samples from plastic surgery and DPC from these follicles did not senesce.

Overexpression of Bmi-1, a suppressor of p16 and p19, extends the replicative lifespan of mouse and human fibroblasts (Jacobs et al., 1999). Therefore, our data showing Bmi-1 expression in non-balding but not in balding DPC correlates with the respective expression of p16INK4a in these cells and provides further evidence that the premature senescence of balding DPC is associated with the p16INK4a pathway and that this may be mediated via downregulation of Bmi-1.

[chore boy]

Inui et al. (2002) have reported that cultured balding DPC secrete more TGF- than non-balding cells. TGF- is known to stimulate oxidative stress in human fibroblasts (Thannickal and Fanburg, 1995). It is therefore possible that increased production of TGF- in vivo in response to androgens may initiate cellular stress responses in balding hair follicles in vivo. Senescent cells are known to have altered patterns of gene expression and secrete a range of growth factors, extracellular matrix proteins, and degradative enzymes (Bavik et al., 2006). These may have a negative impact on hair growth as recently demonstrated by Hamada and Randall (2006) who showed that cultured balding DPC secreted factors that inhibited anagen onset in mice.

[Jacob]

(apple stem cells)

[chore boy]

should be here tomorrow...

I actually have that lipo coq10 on my head as we speak.

[chore boy]

Posted by Kingpin:

Study Showing Telomerase Immortalizes Balding Dermal Papilla

Immortalisation and characterisation of balding and non-balding dermal papilla cell lines and their response to oxidative stress. Adiam W Bahta, Dermatology (QMUL), London, UK
The dermal papilla (DP) expresses androgen receptors and is known to control normal hair growth. The paradox of androgen action in human hair growth is well established but the molecular mechanisms in hair follicles are poorly understood. DP cells derived from frontal (balding) human scalp hair follicles (BDPC) are used to study Androgenetic alopecia. However, cultured BDPC are very difficult to obtain, grow very slowly in vitro and have a limited life span of 2-6 passages before they senescence (see other abstract). We have recently shown that BDPC express senescence-associated beta galactosidase activity at PH-6. Moreover, stress induced premature senescence was induced with more prominent characteristic behaviour in BDPC than non balding DPC (NBDPC) after exposure to sub-cytotoxic levels of H2O2. However, the limited life span of BDPC represents a substantial obstacle for biochemical analysis, genetic manipulation and screens. We therefore, generated immortalized balding and non-balding human DP cells (IBDPC, INBDPC) by ectopic expression of human telomerase. The IBDPC have undergone more than 90 passages without showing any phenotypic changes. As with the primary DPC, the IBDPC maintained their aggregating characteristics and expressed wnt7a, wnt3a, androgen receptor and 5 alpha reductase type 2 mRNA. We established an in vitro co-culture system by growing IBDPC and INBDPC with keratinocytes (KC) to study the androgen effects in hair follicles. Androgen suppressed the growth of KC when grown with IBDPC and this could be partially reversed using a neutralising antibody to TGF-beta1. In addition we have also observed that IBDPC retains increased sensitivity towards H2O2 than INBDPC cell lines. Therefore, immortalised DP cell lines show similar characteristics to primary DPC and they will be of major help to us in our attempt to understand the actions of androgens on hair growth and enable the development of better treatment for androgen dependent hair disorders. ------------------------------------------------------------ Resveratrol only does 3 important things:

1)increases telomerase expression: http://www.ncbi.nlm.nih.gov/pubmed/1796 ... d_RVDocSum

2)interferes with tgf-beta 1: http://www.ncbi.nlm.nih.gov/pubmed/1863 ... d_RVDocSum

http://www.ncbi.nlm.nih.gov/pubmed/1038 ... d_RVDocSum

3)androgen antagonistic: http://www.ncbi.nlm.nih.gov/pubmed/1223 ... d_RVDocSum

[Jacob]

Is that the supplement form of COq10 or the other?

[chore boy]

Supplement... Liqsorb.

[Jacob]

Does it seem to be absorbing well?

[chore boy]

Eh... alright, I suppose. I'm not sure I'd be in a rush to make a daytime topical with it but it's something I could maybe make my last topical of the night, kinda thing.

[jdp710]

I posted this to kingpin awhile back

"Now it appears that falling cellular ATP levels may also result in cellular senescence."

http://ouroboros.wordpress.com...ory/dna-damage-repair/

[jdp710]

Link doesn't work anymore. Here's the whole article.

A glutamine a day keeps senescence away
Posted by ouroboros under DNA damage & repair, Senescence, Sirtuins, Telomeres
No Comments
Cellular senescence is regarded as a tumor suppressor mechanism: damaged cells permanently leave the cell cycle (preventing tumor initiation), and also secrete factors that trigger both tissue repair and inflammation in the vicinity. This is probably good at first but bad later on: persistent senescent cells also secrete growth factors and metalloproteases that degrade the tissue microenvironment and encourage nearby preneoplastic cells to progress into full-blown tumors. Thus, senescence has been implicated in late-life cancer and age-related decline in tissue function.

The "damage" in question is usually genotoxic in nature: telomere shortening, indicating that a cell has undergone many rounds of potentially mutagenic cell division, or high levels of DNA damage such as that resulting from ionizing radiation or exposure to chemical clastogens. Oncogene expression probably also induces senescence via DNA damage, by triggering over-firing of replication origins and generating broken ends and weird chromatin structures that are interpreted as damage.

Now it appears that falling cellular ATP levels may also result in cellular senescence. Unterluggauer et al. report that inhibition of glutaminolysis (preventing cells from generating ATP from glutamine, an unglamorous and occasionally overlooked pathway that is nonetheless an important energy source in many cellular lineages) results in increased senescence in human vascular endothelial cells (HUVECs):

Premature senescence of human endothelial cells induced by inhibition of glutaminase

Cellular senescence is now recognized as an important mechanism of tumor suppression, and the accumulation of senescent cells may contribute to the aging of various human tissues. Alterations of the cellular energy metabolism are considered key events in tumorigenesis and are also known to play an important role for aging processes in lower eukaryotic model systems. In this study, we addressed senescence-associated changes in the energy metabolism of human endothelial cells, using the HUVEC model of in vitro senescence. We observed a drastic reduction in cellular ATP levels in senescent endothelial cells. Although consumption of glucose and production of lactate significantly increased in senescent cells, no correlation was found between both metabolite conversion rates, neither in young endothelial cells nor in the senescent cells, which indicates that glycolysis is not the main energy source in HUVEC. On the other hand, glutamine consumption was increased in senescent HUVEC and inhibition of glutaminolysis by DON, a specific inhibitor of glutaminase, led to a significant reduction in the proliferative capacity of both early passage and late passage cells. Moreover, inhibition of glutaminase activity induced a senescent-like phenotype in young HUVEC within two passages. Together, the data indicate that glutaminolysis is an important energy source in endothelial cells and that alterations in this pathway play a role in endothelial cell senescence.

The authors provide good evidence that endothelial cells rely heavily on glutaminolysis, and that removal of this energy source both drastically reduces cellular ATP levels and results in a "senescent-like" growth arrest. They then show fairly convincingly that this arrest is very similar to the arrest induced by telomere shortening, DNA damage or oncogene expression (i.e., cellular senescence) - in particular, by demonstrating that the arrested HUVECs express a panoply of senescence-associated gene expression and cytological markers. No word, as far as I could tell, on the reversibility of the arrest upon resumption of glutaminolysis (irreversibility is a hallmark of senescence); I mention this because growth arrest is a fairly obviously sensible response to an energy deficit, but it's not clear why it ought to be permanent.

The reason I'm interested in this paper is that it might point toward a unifying principle underlying two major subjects within the field of biogerontology - cellular senescence and sirtuins - which both receive a great deal of individual attention but so far have not been demonstrated to have much to do with one another. Sirtuins such as SIRT1 are regulated by cellular energy state (in particular, by the NAD+/NADH ratio); if it turns out that perturbations in the cellular energy budget are an important means of senescence induction, it might be interesting to take a closer look and see whether sirtuin signaling might influence the establishment of cellular senescence.

[chore boy]

Thanks jdp.

Guess what the hair fairy dropped off?





I put some full-strength on the hairline. Absorbs extremely well. Smells and looks kinda polysorbate 80-ish...

[chore boy]

From Mibelle:

Reversion of Senescence Signs in
Fibroblast Cells

Senescence is a natural process that, after
about 50 divisions, stops the capacity
of the cell to undergo further divisions.
But senescence can also happen
earlier in a cell’s life, for example as response
to damage to the cellular DNA.
Premature senescence is especially detri-mental when it hits stem cells because
they are indispensable for tissue regeneration.
Recently a cellular model for
premature senescence was established
based on fibroblast cells. After a two hour
treatment with H2O2, the cells showed
the typical signs of senescence. This model
was used to prove an anti-senescence
effect of an extract of Uttwiler Spätlauber
stem cells. After the H2O2 treatment,
the fibroblast cells were incubated
with 2% extract for 144 hours.
Then gene expression was analyzed with
a cDNA array system comprising of 150
probes related to cellular growth, signaling,
senescence and aging. Gene expression
was compared to that of cells that
were kept only in the culturemediumafter
the H2O2 treatment. In the control
culture, several genes important for cellular
proliferation and stimulation of
cellular growth were down regulated after
H2O2 treatment (Table 1). Incubation
with the extract of Uttwiler Spätlauber
stem cells neutralized this down regulation
or even induced an up regulation.
The extract also strongly stimulated the
expression of an important antioxidant
enzyme, heme oxigenase 1, whose expression
was surprisingly not increased in the
control.

Retardation of Senescence in
Isolated Hair Follicles
Human hair follicles can be isolated by
microdissection from skin fragments that
are left after facelift surgery. Only follicles
in the anagen phase are collected.
Hair follicles are mini organs that represent
a natural coculture model of epidermal
and melanocyte stem cells and
differentiated cells. The follicles can be
maintained in a growth medium where
they elongate until about day 14. Then
the follicle cells gradually become senescent
or undergo apoptosis which is a
programmed cell death. Because of the
lack of blood circulation, isolated hair
follicles cannot be kept alive and growing
for a longer period. But isolated hair
follicles are test models to screen for actives
that can delay the necrosis process.
Addition of 0.2% of an extract of Uttwiler
Spätlauber stem cells was found
to slightly but clearly postpone senescence-
and apoptosis-induced necrosis.
resistance against senescence and apoptosis
of human stemcells. In thisway, the
plant stem cell extract promotes regeneration
of skin and hair and delays the
appearance of skin aging signs. The exact
mechanism is not known. But the
Uttwiler Spätlauber apples, known to stay
fresh for an extraordinarily long time,
might have stem cells with a special epigenetic
profile. It seems that these epigenetic
factors have a positive effect on
human stem cells.

[chore boy]

http://www.mibellebiochemistry.com/pdfs ... _05_08.pdf

[Jacob]

I KNEW you would use it full strength!

I'm on my second bottle of the Lamas product. I wouldn't mind something for evening use containing the apple stem cells as well..maybe an Elsom product if they ever add it to their Formulator.

[chore boy]

Just like I'm using the lipo Q10 straight, no rubber. Don't even care 'round here.


Dude, I'm stoked hardcore over Phytocelltec and lipo CoQ10. I'm doing my best to not get ahead of myself but I've noticed some very postive things recently that has me wondering if I'm not developing follicularly. Added some Body Shop PO shampoo last week, too.

I noticed that you're slightly salty of me using AN INTERNAL product, externally, but there isn't a doubt in my mind that I'm absorbing it. It's definitely not something to have in your hair when you answer the door... looks like melted orange creamsicle. I figure I'm catching a two-for-one because I was going to be using it for its mitochondria protection properties anyway.

I can't recall exactly why I gave up this potent aloe juice/niacinamide cocktail that I used to use. I would have it in an old Tricomin bottle and spray it in my hair periodically, throughout the day. It's cheap, easy to make and a pleasure to use. I kicked it up last night with a half cap of taurine... sh*t's strong... I couldn't qoute a concentration off the top of my head but I'd have to assume it's at least 15-20%, if not better.

[Jacob]

Don't you think there might be something "negative" about using it full strength? There must be a reason why they give the recommendations they do.

I can't find that liposomal coq10 for cosmetic use I've posted about before- was available for purchase by anyone just like the Phytocelltec product. But this one would be nice to get a hold of: http://www.aquanova.de/media/public/pdf ... 4_09_E.pdf

And Q-gel does make a skin product..so I guess there are some that can be used internally as well as externally. http://www.epic4health.com/skincare.html

[Jacob]

Solgar has it in gelcaps http://www.myvitanet.com/nutri-nano-coq ... olgar.html

[chore boy]

Well... I don't recall there being a percentage quoted for hair loss-desired outcomes and I've seen the Phytocelltec in lotions as high as 20%. I'm planning on making a topical with it and will probably shoot for somewhere around that percentage.