Wednesday, December 12, 2012

Grow tall by lengthening your telomeres?

TA-65, 30 Capsules.  It's expensive but it's supposedly the bestAstragalus is much cheaper but TA-65 may be more effective. They claim that TA-65 increases hTERT activation.  For the first time, in the last study we have a direct connection between telomerase activity and growth.  FGFR3 which causes dwarfism inhibits telomerase activity.  We've always been unclear about whether telomere length can affect height but the authors claim that telomerase and TERT activity independently of telomere length can affect chondrocyte proliferation and therefore height.  TA-65 is more important for open growth plates than closed ones considering the cost as telomerase may not affect initial chondrocyte differentiation.  But since FGFR3 has a huge impact on height and telomerase and TERT play a role in that impact.  TA-65 and astragalus may play a large role in gaining height if taken over time during development.

Previous, DNA Methylation was one method found to control growth plate senescence.  The length of telomere chains may be another way to affect senescence.  Once telomere's have been sufficiently shortened then the cells stop dividing.  DNA Methylation effects all individuals whereas telomere shortening is more important in older individuals(although there may be some telomere shortening in younger individuals).

Sizing the ends: normal length of human telomeres

"The ends of human chromosomes are constituted of telomeres, a nucleoprotein complex. They are mainly formed by the entanglement of repeat DNA and telomeric and non-telomeric proteins. Telomeric sequences are lost in each cell division and this loss happens in vitro as well as in vivo. The diminution of telomere length over the cell cycle has led to the consideration of telomeres as a 'mitotic clock'. Telomere lengths are heterogeneous because they differ among tissues, cells, and chromosome arms. Cell proliferation capacity, cellular environment, and epigenetic factors are elements that affect this telomere heterogeneity. Genetic and environmental factors modulate the difference in telomere lengths between individuals. Telomere length is regulated by telomere structure, telomerase, the enzyme that elongates the 3'-end of telomeres, and alternative lengthening of telomeres (ALT) used exclusively in immortalized and cancer cells."

The average length of telomeres in the bone marrow is 8.5kb.

"Stem cells have been shown to have longer telomeres than progenitor cells."

"Telomeres of bone marrow cells are only 600 bp longer than those of white blood cells"

"The relative length of an individual telomere having the same genetic origin from monozygotic twins is identical. In contrast, relative lengths of homologous individual telomeres of the same individual are different"

"Telomeric loss [is] between 9 and 147 bp per year"

"At each cell division, human telomeres loose 50–200 bp. This telomere loss is due to the ‘end replication problem’ and to telomere processing by nucleases"

"Telomere shortening leads to uncapping of chromosome ends which are then recognized as sites of DNA damaged. This triggers p53 activation that leads to senescence/apoptosis."<-So when there's p53 activity that could be indicative of telomere shortening limiting height growth.

"Telomerase is a ribonucleoprotein which adds telomeric sequences at the 3′-overhang of telomeres"

Regulation of telomerase activity by apparently opposing elements.

"Telomeres, the ends of chromosomes, undergo frequent remodeling events that are important in cell development, proliferation and differentiation, and neoplastic immortalization. Telomerase is a ribonucleoprotein complex that maintains and lengthens telomeres. Hormones, cytokines, ligands of nuclear receptor, vitamins and herbal extracts have significantly influence on telomerase activity and, in some instances, the remodeling of telomeres."

"[Stem Cells] activate telomerase to reverse transcribe telomeric DNA, thereby causing telomere-lengthening."

"The formation of induced pluripotent stem cells (iPS cells) [may require] the activation of telomerase"

"Ectopic expression of TERT is sufficient to restore telomerase activity in telomerase-negative cells and increase cell division in a number of cell types"

"Genistein (Gen) at high and low concentrations inhibits and stimulates STAT3 signaling respectively in regulating telomerase activity."

"Retinoic acid (RA), the oxidized form of vitamin A that retains partial vitamin A function, down-regulates telomerase activity"

"Androgens have been shown to elicit the negative regulation of telomerase activity by inhibition of hTERT expression"

"telomerase activity was increased following androgen castration in rat and monkey"  ERalpha increases telomerase activity.

Cortisol and Dexamethasone inhibit Telomerase activity.  Activin I, TGF-Beta, and BMP7 inhibit telomerase activity.  NGF inhibits telomerase since NGF does not appear to be chondroinductive that may be a good target.

"genistein at physiologically achievable concentrations (0.5–1 μM) stimulates telomerase activity in contrast to its inhibitory effect at a pharmacological concentration (50 μM)"<-which is consistent with estrogen signaling being biphasic.

We'll have to find those vitamins and herbal extracts.  As for hormones...

Androgens stimulate telomerase expression, activity and phosphorylation in ovarian adenocarcinoma cells.

"Androgens significantly increased the viability of ovarian cancer cells and that these hormones induced the expression, activity and phosphorylation of telomerase. This upregulation was blocked by phosphatidylinositol 3-kinase pathway inhibitors."

"androstenedione and testosterone significantly increased telomerase activity in a dose-dependent manner, with maximum effect at concentrations of 100 and 10 nM, respectively"

The PI3K pathway is important in upregulating telomerase activity.  Androgens like testosterone and estrogen induced telomerase activity.  But telomerase alone may not be enough...

Effects of telomerase modulation in human hematopoietic progenitor cells

"Loss of telomeric repeats has been causally linked to replicative senescence and aging in human cells. In contrast to normal somatic cells, which are telomerase-negative, hematopoietic stem cells have low levels of telomerase, which can be transiently upregulated upon cytokine stimulation. To examine whether ectopic expression of telomerase can overcome telomere erosion in hematopoietic progenitor cells, we overexpressed telomerase in CD34+ and AC133+ cord blood (CB) cells using retroviral vectors containing hTERT, the catalytic component of telomerase. Although the hTERT-transduced CB cells exhibited significantly elevated telomerase activity (approximately 10-fold), the mean telomere length was only increased up to 600 bp, which was in contrast to hTERT-transduced fibroblast cells gaining more than 2-kb telomeric repeats. Moreover, ectopic telomerase activity did not prevent overall telomere shortening, which was in the range of 1.3 kb in serum-free expansion culture. We also blocked endogenous telomerase activity by ectopic expression of dominant-negative hTERT. Whereas CB cells with absent telomerase activity showed reduced absolute numbers of colony-forming cells, we observed increased rates only for burst-forming units erythroid when the enzyme was overexpressed. These results suggest that telomere shortening in human hematopoietic progenitor cells cannot be compensated by increased levels of telomerase alone and is likely to be dependent on other factors, such as telomere binding proteins. Furthermore, telomerase function seems to be directly associated with the proliferative capacity of stem cells and may exert an additional role in lineage differentiation."

Telomerase may not be all that is required to prevent telomere shortening but it does increase stem cell proliferative capacity.  Of course exercise has an effect on telomere length...

Leukocyte telomere length is preserved with aging in endurance exercise-trained adults and related to maximal aerobic capacity.

"Telomere length (TL), a measure of replicative senescence, decreases with aging. To determine if age-associated reductions in TL are related to habitual endurance exercise and maximal aerobic exercise capacity (maximal oxygen consumption, VO(2)max), we studied groups of young (18-32 years; n=15, 7 male) and older (55-72 years; n=15, 9 male) sedentary and young (n=10, 7 male) and older (n=17, 11 male) endurance exercise-trained healthy adults. Leukocyte TL (LTL) was shorter in the older (7059+/-141 bp) vs. young (8407+/-218) sedentary adults (P<0.01). LTL of the older endurance-trained adults (7992+/-169 bp) was approximately 900 bp greater than their sedentary peers (P<0.01) and was not significantly different (P=0.12) from young exercise-trained adults (8579+/-413). LTL was positively related to VO(2)max as a result of a significant association in older adults (r=0.44, P<0.01). Stepwise multiple regression analysis revealed that VO(2)max was the only independent predictor of LTL in the overall group."

There may have been some combined factors that influenced telomere length however.

" LTL is not influenced by aerobic exercise status among young subjects, presumably because TL is intact (i.e., already normal) in sedentary healthy young adults"

Now, it could be partially that people with a high VO2 max are more likely to perform aerobic exercise but aerobic exercise has been shown to increase VO2max.  Leukocytes are also called white blood cells which are not stem cells but I think the overall mechanism should be the same.  Caridovascular exercise may help you grow tall by preventing reducting of telomere length by increasing your VO2max.

The effects of regular strength training on telomere length in human skeletal muscle.

"The length of DNA telomeres is an important parameter of the proliferative potential of tissues. A recent study has reported abnormally short telomeres in skeletal muscle of athletes with exercise-associated fatigue. This important report raises the question of whether long-term practice of sports might have deleterious effects on muscle telomeres. Therefore, we aimed to compare telomere length of a group of power lifters (PL; N = 7) who trained for 8 +/- 3 yr against that of a group of healthy, active subjects (C; N = 7) with no history of strength training.
Muscle biopsies were taken from the vastus lateralis, and the mean and minimum telomeric restriction fragments (TRF) (telomere length) were determined, using the Southern blot protocol previously used for the analysis of skeletal muscle.
There was no abnormal shortening of telomeres in PL. On the contrary, the mean (P = 0.07) and the minimum (P = 0.09) TRF lengths in PL tended to be higher than in C. In PL, the minimum TRF length was inversely correlated to the individual records in squat (r = -0.86; P = 0.01) and deadlift (r = -0.88; P = 0.01)."

"mood disorders are associated with accelerated telomere shortening, and it is known that telomere shortening is not an irreversible process, because of the existence of telomerase, an enzyme capable of extending telomeres"

"The heavier the load lifted, the shorter the power lifter's skeletal muscle DNA minimum telomere length."<-maybe PLers who lift heavier weights have more muscle cells and thus more cells that have divided already and thus more cells that are telomere depleted.  What the scientists theory was: "The achievement of a high level of performance in power lifting is associated with a higher level of satellite cell recruitment. Thus, although the minimum telomere length in the athlete population remains within normal physiological ranges, it seems that the heavier the load put on muscles, the shorter the Lmini of the muscles in question. Thus, it can be hypothesized that when the exercise-induced satellite cell recruitment exceeds a given threshold, the telomere length positive regulation becomes ineffective. Interestingly, the number of years of practice and the number of years of competitive power lifting were not associated with minimum telomere length."

Now again it could be that long telomeres means that athletes are more likely to have better records in squats and deadlifts.  Bone like muscle and white blood cells is responsive to load and oxidative stress.  By loading the bone you are increasing the minimum telomere length and increasing the amount of oxygen available to your bone(although oxidative stress may have anabolic effects too).

Unfortunately, the article Regulation of telomerase by apparently opposing elements was not a free article so we can't find what they meant by herbal extracts and vitamins.  Heavy loads and cardio are something we can implement.

Here is a study that suggests that telomere length is not what controls chondrocyte replicative senescence. 

Lack of telomere shortening with age in mouse resting zone chondrocytes.

"Telomeres are hexameric repeat sequences that flank eukaryotic chromosomes. The telomere hypothesis of cellular aging proposes that replication of normal somatic cells leads to progressive telomere shortening which induces replicative senescence. Previous studies suggest that growth plate chondrocytes have a finite proliferative capacity in vivo. We therefore hypothesized that telomere shortening in resting zone chondrocytes leads to replicative senescence.
To test this hypothesis we compared the telomere restriction fragment (TRF) length of Mus casteneus at 1, 4, 8, and 56 weeks of age.We found that TRF length did not diminish measurably with age, suggesting that telomere shortening in resting zone chondrocytes is not the mechanism that limits proliferation of growth plate chondrocytes in vivo."

"among different mammalian species, telomere length does not correlate with skeletal size"<-so longer telomeres may not increase height.

"in humans, telomeres are typically 10–15 kb whereas, in some strains of mice telomeres are approximately 100 kb in length"

"most normal somatic human cells do not express telomerase activity and are unable to maintain telomere length with ongoing cell divisions"

" telomerase-deficient mice do not show abnormalities in skeletal growth. In these mice, telomere length decreases with succeeding generations, and abnormalities begin to occur in some highly proliferative types of cells. However, skeletal growth remains largely unaffected"

The paper Childhood Growth, IQ and Education as Predictors of White Blood Cell Telomere Length at Age 49-51 Years: The Newcastle Thousand Families Study., states that telomere length does not appear to correlate with height in males.

Clonal chondroprogenitors maintain telomerase activity and Sox9 expression during extended monolayer culture and retain chondrogenic potential.

"Chondroprogenitors were isolated from immature bovine metacarpalphalangeal joints by differential adhesion to fibronectin. Cloned colonies were expanded in vitro up to 50 population doublings (PD). Growth characteristics were assessed by cell counts, analysis of telomere length, telomerase activity, expression of senescence-associated beta-galactosidase activity and real-time quantitative polymerase chain reaction to analyse the gene expression patterns of sox9 and Notch-1 in chondroprogenitors.
Cloned chondroprogenitors exhibited exponential growth for the first 20 PD, then slower linear growth with evidence of replicative senescence at later passages. Mean telomere lengths of exponentially growing chondroprogenitors were significantly longer than dedifferentiated chondrocytes that had undergone a similar number of PD (P<0.05). Chondroprogenitors also had 2.6-fold greater telomerase activity. Chondroprogenitors maintained similar sox9 and lower Notch-1 mRNA levels compared to non-clonal dedifferentiated chondrocytes. Chondroprogenitors were induced to differentiate into cartilage in 3D pellet cultures, immunological investigation of sox9, Notch-1, aggrecan and proliferating cell nuclear antigen (PCNA) expression showed evidence of co-ordinated growth and differentiation within the cartilage pellet."

So this study suggests that telomere length can affect growth plate chondrogenesis.

"HES-1 expression in chondroprogenitor populations was 3.68-fold higher than in the parental chondrocyte population"

"sox9 message levels were lower in both clonal chondroprogenitor (3.5-fold; P < 0.001; n = 4) and dedifferentiated chondrocytes (7.7-fold; P < 0.0001; n = 4) compared to full-depth unpassaged cells"

"At every round of cellular division, due to the ‘end replication problem’ where the lagging strand is incompletely synthesised as double-stranded DNA, telomeres are known to shorten by approximately 50–200 bp. We observed that chondroprogenitors maintained their average telomere length, displaying no diminution even after 22 PD when compared to unpassaged parental cells"<-thus they may have had telomerase maintaining their telomere length.

"The telomere erosion rate of chondroprogenitors during this early growth phase, defined as the change in average telomere length as a function of the number of times the cell population has doubled, is 4.5 bp per PD; dedifferentiated chondrocytes have a telomere erosion rate of 166 bp per PD."

"expression of Notch-1 within the cartilage pellets appears to co-ordinate regulated growth and differentiation of chondroprogenitors. Within the cartilage pellets sox9 protein levels increased at the boundary between undifferentiated and differentiated progenitors and we noted intense nuclear labelling of cells within undifferentiated chondroprogenitors. In differentiated progenitors, sox9 protein was distributed equally between cytoplasm and nucleus. The subcellular distribution of sox9 is important in chondrocyte differentiation."


Cell senescence: a challenge in cartilage engineering and regeneration.





"The presence of senescence-associated β-galacotosidase and DNA damage, accumulation of reactive oxygen species, the decline of DNA replication and telomerase activity, and shortened telomere length is indicative of senescence,"

"growth factors, antioxidants, [decellularized stem cell matrix], serum deprivation, or platelet-rich plasma treatment as well as low oxygen have been successful in retarding cell senescence."

Stress can induce senescence before intrinsic factors induce senescence.

"human placenta-derived MSCs underwent aging and spontaneous osteogenic differentiation during regular culture expansion, with down-regulation of human telomerase reverse transcriptase and up-regulation of the osteogenic gene runt-related transcription factor 2 (Runx2) and ALP expression. Stem cell self-renewal associated genes octamer-binding transcription factor 4 (Oct4) and SRY (sex determining region Y)-box 2 (Sox2) expression declined progressively."

"age-related decline in chondrogenic differentiation in BMSCs even with transforming growth factor beta1 (TGF-β1) stimulation, though only in men."

"Senescence-related genes p53, p21, and p16 gradually increase in BMSC long-term culture. As a cell-cycle inhibitor, p21{LSJL downregulates bccip which enhances p21 activity} is closely related with stem cell differentiation capacities"

"The dysregulation of histone H3 acetylation in K9 and K4, but not methylation of CpG islands, was found to be closely associated with gene expression, suggesting that the acetylation-related epigenetic changes also correlate with aging"

"CCN2 interacts with BMP2 through forming a complex that regulates the prehypertrophic and hypertrophic chondrocyte proliferation and differentiation. CCN2 modulates Wnt signaling through binding to the lipoprotein receptor-related protein 6 co-receptor. The expression of CCN2 in chondrocytes is regulated by Rac1 and actin pathways mediated by TGF-β/Smad signaling. In addition, CCN2 and CCN3{LSJL upregulates this 3.563 fold as Nov} exert the opposite effect on regulating proliferation and differentiation in chondrocytes{Note that CCN3 is a positive modulator of chondrogenesis}. CCN4 is a target of the Wnt1 pathway and may function as a promoter of MSC proliferation and osteoblastic differentiation while inhibiting chondrogenic differentiation."

"caveolin-1 overexpression has been correlated with human MSC senescence"

"FGF-2{upregulated by LSJL}, or hepatocyte growth factor, can inhibit IL-1β-induced chondrocyte senescence by down-regulating caveolin-1 expression."

"IGF-I signals through phosphorylation and activation of the protein kinase Akt, which requires binding to heat shock protein 90 (Hsp90) for activation. The level of Hsp90 decreases with aging, which further influences the collagen II and MMP13 expression and results in the dysregulation of cartilage ECM."<-So if HSP90 decreases with aging p-Akt may not increase via LSJL.

"both TLR and NLR agonists[enhancers] could promote human umbilical cord blood-derived MSC chondrogenesis"

Lack of telomerase activity in human mesenchymal stem cells.

"most normal somatic cells are telomerase negative, low levels of this enzyme have been found in adult stem cells from the skin, gut and the hematopoietic system. Here, we show that telomerase activity is not detectable in human mesenchymal stem cells (hMSCs), which have the phenotype SH2+, SH3+, SH4+, CD29+, CD44+, CD14-, CD34- and CD45-, and have the capacity to differentiate into adipocytes, chondrocytes and osteoblasts. These data suggest that hMSCs have a different telomere biology compared to other adult stem cells. true mesenchymal stem cells might be a very rare subpopulation that have a detection level that is below the sensitivity of the TRAP assay."

"no detectable telomerase activity was observed in hMSCs even when a protein concentration of 10 g was used, which corresponds to more than 60 000 cell equivalents"


Telomere length and telomerase activity during expansion and differentiation of human mesenchymal stem cells and chondrocytes.

"Primary chondrocytes and bone-marrow-derived MSC were isolated from 12 donors, expanded separately to 4 x 10(6) cells, and (re-)differentiated as three-dimensional chondrogenic spheroids. Cells were collected during expansion, after three-dimensional culturing and chondrogenic differentiation, and sequential analyses of telomere length and telomerase activity were performed. Telomeres of expanded MSC were significantly shorter than those from expanded chondrocytes from the same donor (11.4+/-2.5 vs. 13.4+/-2.2 kb) and tended to remain shorter after differentiation in chondrogenic spheroids (11.9+/-1.8 vs. 13.0+/- kb). While telomere lengths in native chondrocytes and MSC were not related to the age of the donor, significant negative correlations with age were observed in expanded (136 bp/year), three-dimensionally reconstituted (188 bp/year), and redifferentiated (229 bp/year) chondrocytes. Low levels of telomerase activity were found in MSC and chondrocytes during expansion and after (re-)differentiation to chondrogenic spheroids. In terms of replicative potential, as determined by telomere length, ex vivo expansion followed by chondrogenic differentiation of MSC did not provide a benefit compared to the expansion of adult chondrocytes. Accelerated telomere shortening with age during expansion and redifferentiation argues for an "age phenotype" in chondrocytes as opposed to MSC and suggests an advantage for the use of MSC especially in older individuals and protocols requiring extensive expansion"

Telomere loss in cartilage is low(only 30 bp per year).


Fibroblast growth factor receptor 3 effects on proliferation and telomerase activity in sheep growth plate chondrocytes.

"Fibroblast growth factor receptor 3 (FGFR3) inhibits growth-plate chondrocyte proliferation and limits bone elongation. Gain-of-function FGFR3 mutations cause dwarfism, reduced telomerase activity and shorter telomeres in growth plate chondroyctes suggesting that FGFR3 reduces proliferative capacity, inhibits telomerase, and enhances senescence. Thyroid hormone (T3) plays a role in cellular maturation of growth plate chondrocytes and a known target of T3 is FGFR3. The present study addressed whether reduced FGFR3 expression enhanced telomerase activity, mRNA expression of telomerase reverse transcriptase (TERT) and RNA component of telomerase (TR), and chondrocyte proliferation, and whether the stimulation of FGFR3 by T3 evoked the opposite response.
Sheep growth-plate proliferative zone chondrocytes were cultured and transfected with siRNA to reduce FGFR3 expression; FGFR3 siRNA reduced chondrocyte FGFR3 mRNA and protein resulting in greater proliferation and increased TERT mRNA expression and telomerase activity  {FGFR3 inhibits telomerase}. Chondrocytes treated with T3 significantly enhanced FGFR3 mRNA and protein expression and reduced telomerase activity; TERT and TR were not significantly reduced. The action of T3 at the growth plate may be partially mediated through the FGFR3 pathway.
FGFR3 inhibits chondrocyte proliferation by down-regulating TERT expression and reducing telomerase activity indicating an important role for telomerase in sustaining chondrocyte proliferative capacity during bone elongation."

"Loss-of-function mutations in sheep FGFR3 cause skeletal overgrowth through excessive proliferation of chondrocytes in the growth plate"

"FGFRs, 1, 2 and 4, promote proliferation and are primarily expressed in the perichondrium. FGFR1{up in LSJL} may promote differentiation in the hypertrophic growth plate zone following exit from the proliferative zone "

"Thyroid hormone recruits resting zone growth plate chondrocytes to initiate proliferation but then inhibits further proliferation and induces hypertrophy to accelerate bone aging"

"Sustained proliferation of cells can lead to chromosomal degradation and DNA damage after consecutive replications unless telomere length is maintained"

Telomerase and TERT have a growth promoting effect independently on the effect on telomere maintenance.

"In response to T3 treatment, FGFR3 mRNA was increased" FGFR3 siRNA chondrocytes had 80% more telomerase activity than control.

Lithium inhibits peripheral T3 levels and increases proliferation of stem cells.  These two mechanisms may be related by T3's inhibition of telomerase.

7 comments:

  1. Where is that article?

    I'm studying to become a pharmacist, maybe I can access it through my university (they've bought accounts to a lot of databases)

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  2. Regulation of telomerase activity by apparently opposing elements in Aging Research Review March 2010

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  3. Nope, doesn't look like it :(

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  4. Wow, finally post I can understand lol.

    Tyler, I really admire your hard work and the effort you've put into this research. I have been anonymously following your blog for awhile.

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  5. Good post, how are you doing with LSJL? Any updates?

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  6. Tyler,
    Long time follower, first time poster. Just a few things I'd love your opinion on and that maybe you could post an article for.

    Homeopathic medicines
    baryta carbonica
    symphytum
    silicea

    There have been a lot of reports that people have grown with these post fusion. (the blend that adult height increase is using probably contains these)...

    I'd like for someone who is well done growing to try taking all of the things that show promise in conjunction with each other (Horny goat weed, the homeopathic remedies, SAM-E etc) for one year to see if they have any impact.

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  7. Hi Tyler,

    As for supplements and foods to eat I haven't seen you have written anything about gelatin or bone broth which are extremely important for bone development in addition to the fat solb. vitamins A and D. Just thought I should mention it.

    Some links:

    http://www.ergo-log.com/gelatinegh.html

    http://augmentinforce.50webs.com/Gelatin.htm

    http://www.westonaprice.org/food-features/515-broth-is-beautiful.html

    http://www.westonaprice.org/food-features/513-why-broth-is-beautiful.html

    http://raypeat.com/articles/articles/gelatin.shtml

    http://findarticles.com/p/articles/mi_7396/is_328/ai_n56264937/

    http://www.townsendletter.com/FebMarch2005/broth0205.htm

    http://pathways4health.org/2010/02/05/february-2010-investing-in-stocks/

    One book I really recommend you to read into is Nutrition and Physical Degeneration by Dr. Weston Price. I think it is possible to read that book online now for free.

    -G

    ReplyDelete