...which is all we have left to cling to, since resveratrol did not extend the maximal life spans of lean mice. I'm not sure what compound you are alluding to as a fountain of youth, since so far for mice, resveratrol is not it...
but see this post -- the mice died of lymphoma caused by retrovirus so is suspect. and the resv mice were healthier in old age....
Yes, but lots of drugs will make you healthier in old age without improving maximal life span, so this is a pretty flimsy straw to cling to in the context of maximal life extension. But I agree that it would be nice to have other studies available in a species less genetically predisposed (
endogenous retroviruses are part of the inherited genome) to cancer.
But even if we can find a species where this is the case, the results may be of questionable value. The human genome is known to contain several thousand endogenous retroviruses, some of which are implicated in human cancers and autoimmune diseases, so who knows, this mouse model might actually be a
good model for (a significant subpopulation of) humans in this respect.
Here is a good source, full text available at
http://www.pubmedcen...i?artid=1187282Demystified . . . Human endogenous retrovirusesP N Nelson,1 P R Carnegie,2 J Martin,1 H Davari Ejtehadi,1 P Hooley,1 D Roden,1 S Rowland-Jones,3 P Warren,1 J Astley,1 and P G Murray4
Abstract
Human endogenous retroviruses (HERVs) are a family of viruses within our genome with similarities to present day exogenous retroviruses. HERVs have been inherited by successive generations and it is possible that some have conferred biological benefits. However, several HERVs have been implicated in certain cancers and autoimmune diseases. This article demystifies these retroviruses by providing an insight into HERVs, their means of classification, and a synopsis of HERVs implicated in cancer and autoimmunity. Furthermore, the biological roles of HERVs are explored.
HERVS AND CANCER
Although the precise role(s) of HERVs in the carcinogenic process has not been fully elucidated there are several studies that, if taken together, put forward a convincing argument for the possible involvement of HERVs in malignancy. HERVs may be involved in carcinogenesis by virtue of the expression of HERV mRNA,26 functional proteins,27 or retroviral-like particles.28 They may also be associated with the generation of new promoters29 or the activation of proto-oncogenes.30 The expression of HERV-R mRNA is increased in some cases of small cell lung carcinoma.26 In addition, a teratocarcinoma cell line has been shown to possess a HERV-K sequence and to secrete retroviral-like particles.28 Testicular germ cell tumours (TGCTs) have been shown to contain proteins of the HERV-K family and patients with TGCT often exhibit a specific immune response to gag and env proteins.27,31 It has been suggested that HERV-K may be important in the progression of TGCT through inhibition of an effective immune response,31 and the HERV env genes have been shown to encode immunosuppressive proteins.32,33 It is clear that overexpressed HERV proteins can elicit high titre IgG responses in some settings (for example, HERV-K10 in patients with renal cancer), as detected by the SEREX method (serological identification of expressed genes),34 suggesting that HERV proteins may in the future provide targets for antitumour immunotherapy.
"It has been suggested that HERV-K may be important in the progression of testicular germ cell tumours through inhibition of an effective immune response"
HERV-K might be important in the pathogenesis of human breast cancer. It has been shown that the T47D human mammary carcinoma cell line produces retroviral particles35 with reverse transcriptase activity.36 Both the HERV-K10 related sequences of T47D cells37 and the reverse transcriptase activity36 are increased by steroid hormone treatment, which is thought to be the result of transcriptional activation via binding of the progesterone receptor to regions on the HERV-K genome that correspond to progesterone and glucocorticoid response elements.In choriocarcinoma, it has been shown that a HERV type C is inserted into the human growth factor gene, pleiotrophin (PTN). This results in the generation of a novel tissue specific promoter, which results in the expression of HERV–PTN fusion transcripts, leading to the production of biologically active PTN protein. Expression of the PTN protein (which is normally expressed only at very low amounts in a few normal adult tissues38) appears to be responsible for the aggressive and invasive growth of human choriocarcinoma.29Overexpression is a common mechanism by which proto-oncogenes become activated, leading to subsequent neoplastic transformation.39 In particular, activation of proto-oncogenes of the ras family is common in many tumour types, and some studies have suggested a potential role for HERVs in ras activation. It was shown a methylnitrosourea induced rat mammary carcinoma that insertion of a defective endogenous retrovirus into the intron of c-Ha-ras was responsible for its more than 10 fold overexpression.30
HERVS AND AUTOIMMUNITY
In 1990, an article appeared in the Times newspaper (24 November) with the title "AIDS-like virus may cause arthritis". The report focused on Robert Garry's research that identified retroviral particles in lip biopsies taken from patients with primary Sjogren's syndrome (SS).41 Similarly, in other autoimmune rheumatic diseases, such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), a plethora of articles added to this intriguing observation by providing evidence of retroviral antigens at the site of disease, or the presence of antiretroviral antibodies in the sera of patients.6,42–44 A novel report in 1994 used both PCR (using consensus primers) and serological tests to investigate the presence of retroviruses in a cross section of patients with rheumatoid diseases, including RA, SS, and SLE.45 Interestingly, PCR failed to amplify products relating to HTLV-I or HIV-1, although antibodies to retroviral antigens were detected in the sera of patients. Consequently, there appeared to be a conundrum: antibodies to retroviral products were present but no evidence to implicate exogenous retroviruses could be found. Between 1996 and 1999, some research groups used so called "degenerate" retroviral primers in their PCR reactions.7,46,47 These primers cater for modest variations within two segments common to all retroviruses within the reverse transcriptase encoding pol region and provide an intervening "fingerprint region", which permits DNA sequencing. In brief, these studies7,46,47 revealed nucleotide homologies to endogenous retroviral families, including viruses with similarity to known exogenous retroviruses. Thus, it was plausible that the presence of HERVs could provide an explanation for the presence of antiretroviral antibodies in certain rheumatoid diseases.6,7,48 HERVs have also been implicated in other autoimmune diseases, such as multiple sclerosis (HERV-W, HERV-H) and insulin dependent diabetes mellitus (IDDM) (HERV-K, IDDM22), in addition to inflammatory vascular diseases.49–54 However, in the case of IDDM, subsequent studies55,56 have not been able to confirm this association. Mechanisms whereby HERVs could influence autoimmunity include molecular mimicry (HERVs sharing amino acids common to host proteins), superantigen motifs that bypass the normal MHC restrictive process of T cell stimulation, aberrant expression of antigens, and the presence of neo-antigens, perhaps as a result of HERV and/or exogenous viral combinations.7,32,57–59 The use of animal models has also served to enhance our understanding of endogenous retroviruses. In a lupus model, an 8.4 kbp endogenous retroviral transcript is expressed in affected mice.60 Furthermore, a retroviral element in one of the introns of the fas apoptosis gene appears to alter the splicing of fas transcripts, resulting in a lupus-like autoimmune disease in MRL-lpr/lpr mice.61 Further investigations using animal models and multicentre patient studies are needed to establish links between specific HERVs and autoimmune diseases because many HERVs are also expressed in varying amounts, or in a coordinated fashion, in normal tissues.62,63
"Mechanisms whereby HERVs could influence autoimmunity include molecular mimicry, superantigen motifs that bypass the normal MHC restrictive process of T cell stimulation, aberrant expression of antigens, and the presence of neo-antigens"
Edited by seekonk, 19 June 2009 - 09:21 PM.