http://www.sigg.it/public/doc/GIORNALEART/593.pdf
da leggere in particolare a pag. 4 il capitoletto macroautofagia.
da leggere in particolare a pag. 4 il capitoletto macroautofagia.
per Marlin e Julien, parere
- Thread starter juliensorel
- Start date
Le abitudini si possono in gran parte cambiare con un po' di volontà, ma io preferisco unire l'utile (forse[
]) al dilettevole o minimizzare lo spiacevole. Non arrivo tranquillamente a 24 h di digiuno, ma per 15-17 non ci sono grandi problemi (mi piacerebbe uscissero ricerche che potessero avallare questa mia predisposizione []). Il catabolismo è comunque una questione di punti di vista, per un body builder basta non mangiare per 2-3 ore per catabolizzare i preziosi muscoli.
Quanto all'alito come ti ho detto sopra le cicche (ne basta una, massimo due al giorno) senza zucchero mi pare possano risolvere. Seguendo la zona ho preso l'abitudine di bere l'acqua (che non si sa bene ancora se sia veramente benefica come dicono), ma sento l'esigenza di sostituirla con una bevanda tipo the (o comunque con sostanze utili, tipo Aquarius, ma costicchia...), solo che un the bevanda senza zucchero, dolcificanti o fruttosio temo non esista in commercio (e lungi da me preparami il tutto la sera prima, lo farei per una settimano o due soltanto...). Vuoi vedere che poi basta buttare nell'acqua un po' di cannella per avere una bevanda perfetta allo scopo[]
Per la corsa fai benone, io dopo 1 anno di corsa (sempre 45 min.) una volta la settimana, sono riuscito a raddoppiare alle attuali 2 volte a settimana. Non è una questione di stanchezza, ma di tempo libero, anche se il giorno dopo una corsa non ho voglia di ripeterla, devono passare almeno 2 giorni, ma di solito ne passano appunto tre.
Quest'anno era uscita una ricerca che diceva che un'attività limitata da benefici pari a una intensa e qualcuno ha obiettato che per ridurre del 50% il rischio di cardiopatie servono un centinaio di km a settimana...
Comunque tutte queste cose devono essere fatte con piacere e non subite come obblighi o imposizioni, a me correre piace, così come mi piace l'alimentazione più corretta che seguo da alcuni anni a questa parte.
Ciao
MA - r l i n
]) al dilettevole o minimizzare lo spiacevole. Non arrivo tranquillamente a 24 h di digiuno, ma per 15-17 non ci sono grandi problemi (mi piacerebbe uscissero ricerche che potessero avallare questa mia predisposizione []). Il catabolismo è comunque una questione di punti di vista, per un body builder basta non mangiare per 2-3 ore per catabolizzare i preziosi muscoli.Quanto all'alito come ti ho detto sopra le cicche (ne basta una, massimo due al giorno) senza zucchero mi pare possano risolvere. Seguendo la zona ho preso l'abitudine di bere l'acqua (che non si sa bene ancora se sia veramente benefica come dicono), ma sento l'esigenza di sostituirla con una bevanda tipo the (o comunque con sostanze utili, tipo Aquarius, ma costicchia...), solo che un the bevanda senza zucchero, dolcificanti o fruttosio temo non esista in commercio (e lungi da me preparami il tutto la sera prima, lo farei per una settimano o due soltanto...). Vuoi vedere che poi basta buttare nell'acqua un po' di cannella per avere una bevanda perfetta allo scopo[
]Per la corsa fai benone, io dopo 1 anno di corsa (sempre 45 min.) una volta la settimana, sono riuscito a raddoppiare alle attuali 2 volte a settimana. Non è una questione di stanchezza, ma di tempo libero, anche se il giorno dopo una corsa non ho voglia di ripeterla, devono passare almeno 2 giorni, ma di solito ne passano appunto tre.
Quest'anno era uscita una ricerca che diceva che un'attività limitata da benefici pari a una intensa e qualcuno ha obiettato che per ridurre del 50% il rischio di cardiopatie servono un centinaio di km a settimana...
Comunque tutte queste cose devono essere fatte con piacere e non subite come obblighi o imposizioni, a me correre piace, così come mi piace l'alimentazione più corretta che seguo da alcuni anni a questa parte.
Ciao
MA - r l i n
http://inhumanexperiment.blogspot.com/2008/12/green-tea-black-tea-oolong-tea-increase.html
in questo post - http://inhumanexperiment.blogspot.com/2009/04/lutein-for-skin-elasticity-hydration.html - il blogger in questione scrive di rifornirsi di materie prime presso http://purebulk.com. Ho provato a dare un occhio e i prezzi sembrano molto interessanti.
in questo post - http://inhumanexperiment.blogspot.com/2009/04/lutein-for-skin-elasticity-hydration.html - il blogger in questione scrive di rifornirsi di materie prime presso http://purebulk.com. Ho provato a dare un occhio e i prezzi sembrano molto interessanti.
del resveratrolo ne abbiamo parlato molto a partire dal 2007, se usi il cerca trovarai sicuramente degli approdondimenti. Recenetemente è stato proposto che in ultima analisi anche il resveratrolo agirebbe ttraverso l'attivazione del SIRT1 come un soppressor del mTOR. La stassa curcumina, una altro xenormetico, agirebbe sempre sul mTOR ma in maniere differente, bloccando un cofattore detto Raptor che serve per fare funzionare l'mTOR. Il resveratrolo cmq è molto caro.
Avevamo detto sopra:
mTORC1 is inhibited by low nutrient levels, growth factor deprivation, reductive stress, caffeine, rapamycin, farnesylthiosalicylic acid (FTS) and curcumin.
Mentre è attivato da:
The activity of this complex is stimulated by insulin, growth factors, serum, phosphatidic acid, amino acids (particularly leucine), and oxidative stress.
Tutte cose, forse tranne l'ultima, note per far crescere i capelli...[]
Ciao
MA - r l i n
mTORC1 is inhibited by low nutrient levels, growth factor deprivation, reductive stress, caffeine, rapamycin, farnesylthiosalicylic acid (FTS) and curcumin.
Mentre è attivato da:
The activity of this complex is stimulated by insulin, growth factors, serum, phosphatidic acid, amino acids (particularly leucine), and oxidative stress.
Tutte cose, forse tranne l'ultima, note per far crescere i capelli...[
]Ciao
MA - r l i n
Interessante studio sullo stress ossidativo, che sembra peggiorare la qualità della vita ma non la sua durata. Un punto a favore di Marlin e della sua distinzione tra allungamento della vita (longevità) e allargamento (benessere) della stessa.
J Gerontol A Biol Sci Med Sci. 2009 Sep 23. [Epub ahead of print]
Mice Deficient in Both Mn Superoxide Dismutase and Glutathione
Peroxidase-1 Have Increased Oxidative Damage and a Greater Incidence
of Pathology but No Reduction in Longevity.
Zhang Y, Ikeno Y, Qi W, Chaudhuri A, Li Y, Bokov A, Thorpe SR, Baynes
JW, Epstein C, Richardson A, Van Remmen H.
Barshop Institute for Longevity and Aging Studies, University of Texas
Health Science Center at San Antonio, 15355 Lambda Drive, San Antonio,
TX 78245. vanremmen@@@uthscsa.edu.
To test the impact of increased mitochondrial oxidative stress as a
mechanism underlying aging and age-related pathologies, we generated
mice with a combined deficiency in two mitochondrial-localized
antioxidant enzymes, Mn superoxide dismutase (MnSOD) and glutathione
peroxidase-1 (Gpx-1). We compared life span, pathology, and oxidative
damage in Gpx1(-)(/-), Sod2(+/-)Gpx1(+/-), Sod2(+/-)Gpx1(-)(/-), and
wild-type control mice. Oxidative damage was elevated in Sod2(+/-)Gpx1
(-)(/-) mice, as shown by increased DNA oxidation in liver and
skeletal muscle and increased protein oxidation in brain.
Surprisingly, Sod2(+/-)Gpx1(-)(/-) mice showed no reduction in life
span, despite increased levels of oxidative damage. Consistent with
the important role for oxidative stress in tumorigenesis during aging,
the incidence of neoplasms was significantly increased in the older
Sod2(+/-)Gpx1(-)(/-) mice (28-30 months). Thus, these data do not
support a significant role for increased oxidative stress as a result
of compromised mitochondrial antioxidant defenses in modulating life
span in mice and do not support the oxidative stress theory of aging.
PMID: 19776219 [PubMed - as supplied by publisher]
J Gerontol A Biol Sci Med Sci. 2009 Sep 23. [Epub ahead of print]
Mice Deficient in Both Mn Superoxide Dismutase and Glutathione
Peroxidase-1 Have Increased Oxidative Damage and a Greater Incidence
of Pathology but No Reduction in Longevity.
Zhang Y, Ikeno Y, Qi W, Chaudhuri A, Li Y, Bokov A, Thorpe SR, Baynes
JW, Epstein C, Richardson A, Van Remmen H.
Barshop Institute for Longevity and Aging Studies, University of Texas
Health Science Center at San Antonio, 15355 Lambda Drive, San Antonio,
TX 78245. vanremmen@@@uthscsa.edu.
To test the impact of increased mitochondrial oxidative stress as a
mechanism underlying aging and age-related pathologies, we generated
mice with a combined deficiency in two mitochondrial-localized
antioxidant enzymes, Mn superoxide dismutase (MnSOD) and glutathione
peroxidase-1 (Gpx-1). We compared life span, pathology, and oxidative
damage in Gpx1(-)(/-), Sod2(+/-)Gpx1(+/-), Sod2(+/-)Gpx1(-)(/-), and
wild-type control mice. Oxidative damage was elevated in Sod2(+/-)Gpx1
(-)(/-) mice, as shown by increased DNA oxidation in liver and
skeletal muscle and increased protein oxidation in brain.
Surprisingly, Sod2(+/-)Gpx1(-)(/-) mice showed no reduction in life
span, despite increased levels of oxidative damage. Consistent with
the important role for oxidative stress in tumorigenesis during aging,
the incidence of neoplasms was significantly increased in the older
Sod2(+/-)Gpx1(-)(/-) mice (28-30 months). Thus, these data do not
support a significant role for increased oxidative stress as a result
of compromised mitochondrial antioxidant defenses in modulating life
span in mice and do not support the oxidative stress theory of aging.
PMID: 19776219 [PubMed - as supplied by publisher]
http://ouroboros.wordpress.com/2009/09/17/rip-for-mfrta/
valgono le obiezione in fondo, in seguito alla citazione in corsivo.
I doubt very much that this article will put a permanent end to the controversy. Data reported fairly recently have breathed new life into oxidative theories in general and the MFRTA (mitochondrial free radical theory of aging) in particular. While these authors contend that the CLK-1 mouse mutant contradicts the underlying mechanisms of the MFRTA, other recently reported work on this pathway supports the claim that inhibiting mitochondrial respiration delays aging, a key prediction of MFRTA.
Furthermore, if mitochondrially generated oxidative radicals are truly not playing a causative role in aging, it becomes much harder to explain how mitochondrially targeted antioxidants can extend lifespan in mammals.
valgono le obiezione in fondo, in seguito alla citazione in corsivo.
I doubt very much that this article will put a permanent end to the controversy. Data reported fairly recently have breathed new life into oxidative theories in general and the MFRTA (mitochondrial free radical theory of aging) in particular. While these authors contend that the CLK-1 mouse mutant contradicts the underlying mechanisms of the MFRTA, other recently reported work on this pathway supports the claim that inhibiting mitochondrial respiration delays aging, a key prediction of MFRTA.
Furthermore, if mitochondrially generated oxidative radicals are truly not playing a causative role in aging, it becomes much harder to explain how mitochondrially targeted antioxidants can extend lifespan in mammals.
Per restare più in tema, un articolo sull'uomo più vecchio del mondo, e guarda un po' il suo suggerimento è: due pasti al giorno (e una baby aspirina).
Two-meal diet aids in oldest man's longevity
By Sydne George, Great Falls (Mont.) Tribune
GREAT FALLS, Mont. — So what does the world's oldest man eat? The answer is not much, at least not too much.
Walter Breuning, who turned 113 on Monday, eats just two meals a day and has done so for the past 35 years.
I think you should push back from the table when you're still hungry, Breuning said.
At 5 foot 8, (I shrunk a little, he admitted) and 125 pounds, Breuning limits himself to a big breakfast and lunch every day and no supper.
I have weighed the same for about 35 years, Breuning said. Well, that's the way it should be.
You get in the habit of not eating at night, and you realize how good you feel. If you could just tell people not to eat so darn much.
His practice of skipping supper began when he first moved to Great Falls from Minneapolis in 1978. He lived in the Yellowstone Apartments at the time and would walk downtown to Schell's in the Johnson Hotel or the Albon Club on the second floor for lunch.
In 1980, the Albon Club moved to the Rainbow Hotel, and the owners asked Breuning to be manager, which he did for 15 years.
I never started eating supper again, Breuning said.
He gets up at 6:15 a.m. and has a big breakfast every day at 7:30 a.m. Usually it's eggs, toast or pancakes.
You can order anything you want, just like a restaurant, he said.
I eat a lot of fruit every day.
Montana Gov. Brian Schweitzer sent Breuning a fruit basket after a recent visit.
Boy, I tell you that was good fruit. I ate the whole darn thing, Breuning said. Peaches, pears, everything, it sure was good.
In addition to eating fruit every day, Breuning also takes a baby aspirin.
Just one baby aspirin, he said, but everybody gets that for their heart. That's the only pill I ever take, no other medicine.
And he drinks plenty of water.
I drink water all the time, he said, and just a bit of coffee. I drink a cup and a half of coffee for breakfast and a cup with lunch.
Breuning said he has been healthy all of his life and believes diet has a lot to do with it.
If people could cut back on their normal weight, it wouldn't be quite so bad, he commented. They just eat too much!
Breuning remembers his family having a cow, pigs, chickens and a big garden when he was growing up, like most people did in those days.
Everybody was poor years ago, he said. When we were kids, we ate what was on the table. Crusts of bread or whatever it was. You ate what they put on your plate, and that's all you got, Breuning said.
Breuning recalls his mother being a good cook, though she died when she was 46 after an operation in Minneapolis. His wife was a good cook, too. They met when they worked in Butte for the railroad.
Everything she made was good, Breuning said. We used to have lots of card parties, and they would always say what a good cook she was.
While diet has contributed to his longevity, Breuning also believes that working hard was good for him.
Work doesn't hurt anybody, he said, mentioning that he had two jobs, one working for the Great Northern Railway until he was 66 and the other as manager/secretary for the local Shriner's Club until he was 99.
These days, Breuning keeps busy talking with all of the people who visit the Rainbow Retirement Center interested in meeting the world's oldest man.
Though his vision doesn't allow him to read anymore, Breuning keeps his mind active by listening to the radio.
My eyes are gone, he said, but I listen to the radio. I get all my news on KMON.
Breuning started eating out 35 years ago, but said he doesn't anymore.
Once you get used to not eating in restaurants, you don't want to anymore, he said. Besides, he'd rather eat at home, at the Rainbow Retirement Center.
They have a lot of good food right here, he said, and good cooks.
Breuning celebrated his 113th birthday with not one, but two cakes, one chocolate and one vanilla. And for his birthday lunch he got his favorite: liver and onions.
Two-meal diet aids in oldest man's longevity
By Sydne George, Great Falls (Mont.) Tribune
GREAT FALLS, Mont. — So what does the world's oldest man eat? The answer is not much, at least not too much.
Walter Breuning, who turned 113 on Monday, eats just two meals a day and has done so for the past 35 years.
I think you should push back from the table when you're still hungry, Breuning said.
At 5 foot 8, (I shrunk a little, he admitted) and 125 pounds, Breuning limits himself to a big breakfast and lunch every day and no supper.
I have weighed the same for about 35 years, Breuning said. Well, that's the way it should be.
You get in the habit of not eating at night, and you realize how good you feel. If you could just tell people not to eat so darn much.
His practice of skipping supper began when he first moved to Great Falls from Minneapolis in 1978. He lived in the Yellowstone Apartments at the time and would walk downtown to Schell's in the Johnson Hotel or the Albon Club on the second floor for lunch.
In 1980, the Albon Club moved to the Rainbow Hotel, and the owners asked Breuning to be manager, which he did for 15 years.
I never started eating supper again, Breuning said.
He gets up at 6:15 a.m. and has a big breakfast every day at 7:30 a.m. Usually it's eggs, toast or pancakes.
You can order anything you want, just like a restaurant, he said.
I eat a lot of fruit every day.
Montana Gov. Brian Schweitzer sent Breuning a fruit basket after a recent visit.
Boy, I tell you that was good fruit. I ate the whole darn thing, Breuning said. Peaches, pears, everything, it sure was good.
In addition to eating fruit every day, Breuning also takes a baby aspirin.
Just one baby aspirin, he said, but everybody gets that for their heart. That's the only pill I ever take, no other medicine.
And he drinks plenty of water.
I drink water all the time, he said, and just a bit of coffee. I drink a cup and a half of coffee for breakfast and a cup with lunch.
Breuning said he has been healthy all of his life and believes diet has a lot to do with it.
If people could cut back on their normal weight, it wouldn't be quite so bad, he commented. They just eat too much!
Breuning remembers his family having a cow, pigs, chickens and a big garden when he was growing up, like most people did in those days.
Everybody was poor years ago, he said. When we were kids, we ate what was on the table. Crusts of bread or whatever it was. You ate what they put on your plate, and that's all you got, Breuning said.
Breuning recalls his mother being a good cook, though she died when she was 46 after an operation in Minneapolis. His wife was a good cook, too. They met when they worked in Butte for the railroad.
Everything she made was good, Breuning said. We used to have lots of card parties, and they would always say what a good cook she was.
While diet has contributed to his longevity, Breuning also believes that working hard was good for him.
Work doesn't hurt anybody, he said, mentioning that he had two jobs, one working for the Great Northern Railway until he was 66 and the other as manager/secretary for the local Shriner's Club until he was 99.
These days, Breuning keeps busy talking with all of the people who visit the Rainbow Retirement Center interested in meeting the world's oldest man.
Though his vision doesn't allow him to read anymore, Breuning keeps his mind active by listening to the radio.
My eyes are gone, he said, but I listen to the radio. I get all my news on KMON.
Breuning started eating out 35 years ago, but said he doesn't anymore.
Once you get used to not eating in restaurants, you don't want to anymore, he said. Besides, he'd rather eat at home, at the Rainbow Retirement Center.
They have a lot of good food right here, he said, and good cooks.
Breuning celebrated his 113th birthday with not one, but two cakes, one chocolate and one vanilla. And for his birthday lunch he got his favorite: liver and onions.
Va anche detto che di solito gli anziani tendono a mangiare poco.
Ho l'esempio di mio padre che a 40 anni era obeso (100 kg per 1,76 cm), quindi è sceso negli anni successivi e ora è un vecchietto di 87 anni piuttosto secco. Era un mangione e ora mangia poco. Era pure un buon fumatore e ora non fuma più.
Quest'anno si è pure beccato una broncopolmonite, ricoverato, è riuscito a sfangarla in un mese di ospedale.
Purtroppo non è più autonomo nella locomozione da qualche anno (ed era un gran camminatore).
Però ha un cugino di 6 mesi più anziano che fa tutta un'altra vita, vedovo da poco, ha una donna di 60 anni (18 anni più giovane), ha sempre giocato a tennis e lo fa ancora, non ha mai fumato. E' sempre stato alto e magro e anche con un mucchio di capelli.
Ciao
MA - r l i n
Ho l'esempio di mio padre che a 40 anni era obeso (100 kg per 1,76 cm), quindi è sceso negli anni successivi e ora è un vecchietto di 87 anni piuttosto secco. Era un mangione e ora mangia poco. Era pure un buon fumatore e ora non fuma più.
Quest'anno si è pure beccato una broncopolmonite, ricoverato, è riuscito a sfangarla in un mese di ospedale.
Purtroppo non è più autonomo nella locomozione da qualche anno (ed era un gran camminatore).
Però ha un cugino di 6 mesi più anziano che fa tutta un'altra vita, vedovo da poco, ha una donna di 60 anni (18 anni più giovane), ha sempre giocato a tennis e lo fa ancora, non ha mai fumato. E' sempre stato alto e magro e anche con un mucchio di capelli.
Ciao
MA - r l i n
Bello questo riepilogo di tutte le più recenti scoperte geniche riguardante la formazione dei follicoli che qui sono esposte in modo piuttosto chiaro e sequenziale.
Interessante pure la correlazione con il carcinoma delle cellule basali che è il più diffuso tra gli occidentali colpendo il 30% della popolazione:
http://en.wikipedia.org/wiki/Basal_cell_carcinoma
Difficile dopo la lettura di questo studio riepilogativo pensare ancora a complotti mirati a non risolvere il problema dell'aga, vista la complessità che presenta la rigenerazione dei follicoli.
Ciao
MA - r l i n
Interessante pure la correlazione con il carcinoma delle cellule basali che è il più diffuso tra gli occidentali colpendo il 30% della popolazione:
http://en.wikipedia.org/wiki/Basal_cell_carcinoma
Difficile dopo la lettura di questo studio riepilogativo pensare ancora a complotti mirati a non risolvere il problema dell'aga, vista la complessità che presenta la rigenerazione dei follicoli.
Ciao
MA - r l i n
http://www.ilgiornale.it/esteri/nobel_medicina_a_ricercatori_americani_scoperte_longevita/comosomi-longevita-premio_nobel-medicina/05-10-2009/articolo-id=388403-page=0
Mi hai preceduto di un'oretta circa. Avevo visto la notizia del Nobel per la medicina sul sito del Corriere, ma non avevo approfondito nel merito, poi salito in macchina per la pausa pranzo ho sentito per radio che il Nobel veniva dato per la scoperta di telomeri e telomerasi e mi sono detto poi lo posto sul forum....
Bene speriamo serva ad approfondire tutta la questione.
Anche perchè il dibattito nei forum specializzati va avanti ed è sempre più appassionante, visto che ci sarebbe una molecola segreta quella della TA-65, che si sa solo che viene dall'astragalo, ma si sta facendo di tutto per non rivelare esattamente quale sia. Si dice solo che è presente in basse percentuali.
Comunque a mio avviso prendere gli estratti di astragalo va comunque in questo senso (parlo di estratti non di radice semplice), alzano le difese immunitarie e lo fanno molto probabilmente con questo meccanismo, inoltre contengono selenio che è un altro telomerase activator, infine contengono la stragrande maggioranza delle molecole citate nello studio Geron come attivatori della telomerasi, saranno tutte in basse quantità, ma si sa che la sinergia di più principi attivi nei fitoterapici è spesso vincente.
Ciao
MA - r l i n
Bene speriamo serva ad approfondire tutta la questione.
Anche perchè il dibattito nei forum specializzati va avanti ed è sempre più appassionante, visto che ci sarebbe una molecola segreta quella della TA-65, che si sa solo che viene dall'astragalo, ma si sta facendo di tutto per non rivelare esattamente quale sia. Si dice solo che è presente in basse percentuali.
Comunque a mio avviso prendere gli estratti di astragalo va comunque in questo senso (parlo di estratti non di radice semplice), alzano le difese immunitarie e lo fanno molto probabilmente con questo meccanismo, inoltre contengono selenio che è un altro telomerase activator, infine contengono la stragrande maggioranza delle molecole citate nello studio Geron come attivatori della telomerasi, saranno tutte in basse quantità, ma si sa che la sinergia di più principi attivi nei fitoterapici è spesso vincente.
Ciao
MA - r l i n
estratto da Pharmacological intervention strategies for affecting telomerase activity: Future prospects to treat cancer and degenerative disease I. Tárkányia and J. Aradib, c, ,
a3rd Department of Internal Medicine, University of Debrecen, 22 Moricz Zsigmond Krt., Debrecen 4004, Hungary
bDepartment of Biochemistry and Molecular Biology, University of Debrecen, 1 Egyetem tér, Debrecen 4010, Hungary
cResearch Center for Molecular Medicine, Medical and Health Science Center, University of Debrecen, 1 Egyetem tér, Debrecen 4010, Hungary
Received 12 June 2007; accepted 4 September 2007. Available online 11 September 2007.
4.2. Activation of endogenous hTERT expression
Telomerase promoter reprogramming, in order to reactivate the production of repressed hTERT, would be the most physiological way to a controlled elevation of telomerase activity. Differentiation induced telomerase repression is predominantly due to the transcriptional downregulation of hTERT expression, governed by complicated regulatory pathways [reviewed in [29]] and influenced by epigenetic mechanisms as well [151]. Histone deacetylase inhibitors were shown to reactivate telomerase in adult mesenchymal cells [152]. Raloxifene, a selective estrogen receptor modulator, could induce hTERT expression, and enhanced its activity by promoting phosphorylation trough Akt cascade, as well as association with NF#954;B [153].
4.3. Enhancing telomerase activity
Despite the fact that usage of telomerase activator molecules, interacting directly the telomerase enzyme, could be clinically the safest method to activate telomerase, their number is surprisingly modest. One of the limitations is that their therapeutic effect can be exerted only in tissues with the presents of residual telomerase activity. Recent findings support that stem cells of regenerative tissues belong to the possible targets fulfilling the above described conditions; they do contain low level of telomerase activity. Lymphocytes could also be ideal targets for the treatment with telomerase activators, since they have a low level telomerase activity when unstimulated, which increases during activation-induced clonal expansion, mainly by enzyme phosphorylation causing nuclear translocation [154]. Upon repeated stimulation, either as a consequence of the antigen challenge or simply because of the age of the host organism, T-cells progressively lose their ability to induce telomerase activity, resulting in replicative senescence in the highly differentiated memory T-cell population [reviewed in [155]]. Individuals with lymphocytes possessing low telomerase activity following antigen encounter, will thus experience an exhaustion of their memory cells and decline of their immune system. Molecules increasing telomerase activity could restore their proliferative capacity as well as some other functions. Augmentation of telomerase activity can be achieved by direct and indirect pharmacological intervention. The previous is represented by molecules interacting with the telomerase holoenzyme while latter comprises agents influencing telomerase activity by affecting gene expression at different levels.
One of the most promising trials for directly acting small-molecule telomerase activators was presented at the conference “The Biology of Ageing” (2006, Ventura, California). The telomerase activator molecules TAT0001 and TAT0002 (Geron®) were shown to improve proliferative response of CD8+ T-cells, and augmented their interferone#947; production. Thus the cells had enhanced ability to inhibit viral replication when co-cultured with HIV infected CD4+ cells. The company announced to be in the process to apply for the approvals to start Phase I/II clinical trials.
TA-65®, a telomerase activator agent derived from the Chinese Astragalus plant, is licensed to Telomerase Activation Sciences and Geron, has already been tested in a pivotal clinical study, and showed to improve immune function, eye sight, sexual function and skin characteristics. This product, told to be available on the market in 2007, is planned to be sold as a food supplement (see company's website).
Although telomere or telomerase specific agents are rare, several agents are known to counteract senescence in an indirect but telomere/telomerase dependent way. Endothelial cells as well as vascular smooth muscle cells have a low telomerase activity. It has been demonstrated several years ago, that hTERT introduction into human endothelial cells can extend their lifespan [143]. Since application of gene therapy for the treatment of general atherosclerosis seems to be unrealizable for the moment, pharmacological agents augmenting telomerase activity could be applied advantageously. Mitochondrial dysfunction causing elevated production of mitochondrial reactive oxygen species has been assigned to be the major determinant of telomere-dependent senescence at the single-cell level that is responsible for cell-to-cell variation in replicative lifespan [156]. Antioxidants have been proven to delay the onset of vascular senescence in a telomerase dependent way. In an in vitro study the reactive oxygen species (ROS) were shown to decrease the level of nuclear hTERT protein and telomerase activity in endothelial cells, which was followed by the early onset of senescent phenotype, while incubation with the antioxidant N-acetylcysteine blocked this nuclear export of hTERT into the cytosol [157]. #945;-Tocopherol, another well known antioxidant, has also been shown to repress telomere shortening and retain telomerase activity in brain microvascular endotheliocytes [158].
More interesting findings reported about telomere-dependent delay of senescence following HMG-CoA reductase inhibitor therapy. Partially fitting into the above theory, statins seem to interfere with the redox balance of endothelial cells [157]. Another potential mechanism could be the elevated expression of TRF2, a telomere binding protein, which is thought to stabilize the telomeric structure at the t-loop [159]. A recent study, with 484 individuals participating in the West Scotland Primary Prevention Study (WOSCOPS), showed that treatment of patients with statin is associated with a reduction in the number of cardiovascular clinical events in individuals with increased risk indicated by short lymphocyte telomere length [160]. Besides synthetic molecules, natural products were tested as well. Ginko Biloba extract was shown to delay the onset of senescence through activating telomerase via PI3k/Akt signaling pathway [161].
In the last decades successful therapies were developed for acute diseases, like infections and injuries increasing the relative prevalence of incurable chronic degenerative illnesses of cardiovascular and central nervous system. Therapies targeting these chronic diseases should include treatments for tissue regeneration, which process may be promoted by telomerase activating agents. Thus, there is an urgent need for telomerase activators, preferably small molecules, which may be included in the armament of therapy against degenerative diseases in the near future.
a3rd Department of Internal Medicine, University of Debrecen, 22 Moricz Zsigmond Krt., Debrecen 4004, Hungary
bDepartment of Biochemistry and Molecular Biology, University of Debrecen, 1 Egyetem tér, Debrecen 4010, Hungary
cResearch Center for Molecular Medicine, Medical and Health Science Center, University of Debrecen, 1 Egyetem tér, Debrecen 4010, Hungary
Received 12 June 2007; accepted 4 September 2007. Available online 11 September 2007.
4.2. Activation of endogenous hTERT expression
Telomerase promoter reprogramming, in order to reactivate the production of repressed hTERT, would be the most physiological way to a controlled elevation of telomerase activity. Differentiation induced telomerase repression is predominantly due to the transcriptional downregulation of hTERT expression, governed by complicated regulatory pathways [reviewed in [29]] and influenced by epigenetic mechanisms as well [151]. Histone deacetylase inhibitors were shown to reactivate telomerase in adult mesenchymal cells [152]. Raloxifene, a selective estrogen receptor modulator, could induce hTERT expression, and enhanced its activity by promoting phosphorylation trough Akt cascade, as well as association with NF#954;B [153].
4.3. Enhancing telomerase activity
Despite the fact that usage of telomerase activator molecules, interacting directly the telomerase enzyme, could be clinically the safest method to activate telomerase, their number is surprisingly modest. One of the limitations is that their therapeutic effect can be exerted only in tissues with the presents of residual telomerase activity. Recent findings support that stem cells of regenerative tissues belong to the possible targets fulfilling the above described conditions; they do contain low level of telomerase activity. Lymphocytes could also be ideal targets for the treatment with telomerase activators, since they have a low level telomerase activity when unstimulated, which increases during activation-induced clonal expansion, mainly by enzyme phosphorylation causing nuclear translocation [154]. Upon repeated stimulation, either as a consequence of the antigen challenge or simply because of the age of the host organism, T-cells progressively lose their ability to induce telomerase activity, resulting in replicative senescence in the highly differentiated memory T-cell population [reviewed in [155]]. Individuals with lymphocytes possessing low telomerase activity following antigen encounter, will thus experience an exhaustion of their memory cells and decline of their immune system. Molecules increasing telomerase activity could restore their proliferative capacity as well as some other functions. Augmentation of telomerase activity can be achieved by direct and indirect pharmacological intervention. The previous is represented by molecules interacting with the telomerase holoenzyme while latter comprises agents influencing telomerase activity by affecting gene expression at different levels.
One of the most promising trials for directly acting small-molecule telomerase activators was presented at the conference “The Biology of Ageing” (2006, Ventura, California). The telomerase activator molecules TAT0001 and TAT0002 (Geron®) were shown to improve proliferative response of CD8+ T-cells, and augmented their interferone#947; production. Thus the cells had enhanced ability to inhibit viral replication when co-cultured with HIV infected CD4+ cells. The company announced to be in the process to apply for the approvals to start Phase I/II clinical trials.
TA-65®, a telomerase activator agent derived from the Chinese Astragalus plant, is licensed to Telomerase Activation Sciences and Geron, has already been tested in a pivotal clinical study, and showed to improve immune function, eye sight, sexual function and skin characteristics. This product, told to be available on the market in 2007, is planned to be sold as a food supplement (see company's website).
Although telomere or telomerase specific agents are rare, several agents are known to counteract senescence in an indirect but telomere/telomerase dependent way. Endothelial cells as well as vascular smooth muscle cells have a low telomerase activity. It has been demonstrated several years ago, that hTERT introduction into human endothelial cells can extend their lifespan [143]. Since application of gene therapy for the treatment of general atherosclerosis seems to be unrealizable for the moment, pharmacological agents augmenting telomerase activity could be applied advantageously. Mitochondrial dysfunction causing elevated production of mitochondrial reactive oxygen species has been assigned to be the major determinant of telomere-dependent senescence at the single-cell level that is responsible for cell-to-cell variation in replicative lifespan [156]. Antioxidants have been proven to delay the onset of vascular senescence in a telomerase dependent way. In an in vitro study the reactive oxygen species (ROS) were shown to decrease the level of nuclear hTERT protein and telomerase activity in endothelial cells, which was followed by the early onset of senescent phenotype, while incubation with the antioxidant N-acetylcysteine blocked this nuclear export of hTERT into the cytosol [157]. #945;-Tocopherol, another well known antioxidant, has also been shown to repress telomere shortening and retain telomerase activity in brain microvascular endotheliocytes [158].
More interesting findings reported about telomere-dependent delay of senescence following HMG-CoA reductase inhibitor therapy. Partially fitting into the above theory, statins seem to interfere with the redox balance of endothelial cells [157]. Another potential mechanism could be the elevated expression of TRF2, a telomere binding protein, which is thought to stabilize the telomeric structure at the t-loop [159]. A recent study, with 484 individuals participating in the West Scotland Primary Prevention Study (WOSCOPS), showed that treatment of patients with statin is associated with a reduction in the number of cardiovascular clinical events in individuals with increased risk indicated by short lymphocyte telomere length [160]. Besides synthetic molecules, natural products were tested as well. Ginko Biloba extract was shown to delay the onset of senescence through activating telomerase via PI3k/Akt signaling pathway [161].
In the last decades successful therapies were developed for acute diseases, like infections and injuries increasing the relative prevalence of incurable chronic degenerative illnesses of cardiovascular and central nervous system. Therapies targeting these chronic diseases should include treatments for tissue regeneration, which process may be promoted by telomerase activating agents. Thus, there is an urgent need for telomerase activators, preferably small molecules, which may be included in the armament of therapy against degenerative diseases in the near future.
Ok, Julien, del Ginkgo pro-telomerasi sapevo, interessante sapere che anche NAC e tocoferolo (vit.E) hanno lo stesso effetto. Aggiungo il selenio (ma l'ho detto sopra) e penso sia anche il caso di composti di piante tipo l'Ashwaganda, la Fumaria, l'Echinacea etc, ma è una mia supposizione.
Piuttosto guarda questo studio recentissimo.
http://www.sciencedaily.com/releases/2009/09/090930084602.htm
MAPK, Notch e TGF-beta, tutte vecchie conoscenze di chi si è addentrato nella problematica aga, con il ruolo dei buoni per i primi due e quasi sempre del cattivo per il secondo. Proprio come in questi importanti esperimenti sul tessuto muscolare di giovani e anziani.
Ciao
MA - r l i n
Piuttosto guarda questo studio recentissimo.
http://www.sciencedaily.com/releases/2009/09/090930084602.htm
MAPK, Notch e TGF-beta, tutte vecchie conoscenze di chi si è addentrato nella problematica aga, con il ruolo dei buoni per i primi due e quasi sempre del cattivo per il secondo. Proprio come in questi importanti esperimenti sul tessuto muscolare di giovani e anziani.
Ciao
MA - r l i n
ma mi viene da pensare che forse nello scalpo questa capacità rigenerativa sotto l'azione genomica degli androgeni venga meno, sotto lo stimolo del TGF-Beta. Provo a vadere MAPK e androgenetic alopecia. Anche se i muscoli sono tessuti differenti dagli annessi cutanei.
http://linkinghub.elsevier.com/retrieve/pii/S0923181103002706 se ti scarichi questo dovrebbe parlare dei rapporti tra MAPK e TGF-Beta2