FOXO4 D-Retro-Inverso is identical to the protein product of the FOXO4 gene, but the normal L amino acids have been exchanged for D amino acids. The result is that FOXO4-DRI has reduced susceptibility to normal physiologic clearance mechanisms and thus remains in the body for longer periods of time. The modified protein is still capable, however, of affecting transcription and cellular pathways. In general, the FOXO4-DRI protein interferes with normal FOXO4 function.
Of greatest interest in terms of aging and senescence is the ability of FOXO4-DRI to interfere with normal FOXO4 signaling in the cell cycle by preventing the binding of FOXO4 to p53. The p53 protein is an important regulator of progression through the cell cycle as well as programmed cell death (apoptosis). When FOXO4-DRI binds to p53, it prevents FOXO4 from binding and allows p53 to bind to DNA. This, in turn, allows the cell to continue through the process of apoptosis and die. Interestingly, FOXO4-DRI appears to only have this effect in senescent cells, cells that are no longer functional or are dysfunctional as a result of aging[2]. By targeting these dysfunctional cells, FOXO4-DRI helps to rid tissue of cells that are nothing but dead weight. This, in turn, allows for better tissue functioning and helps to stimulate growth and differentiation of younger, healthier cells. The net result is better biological function and thus a decrease in “biological age”.
Sequence
H-D-Leu-D-Thr-D-Leu-D-Arg-D-Lys-D-Glu-D-Pro-D-Ala-D-Ser-D-Glu-D-Ile-D-Ala-D-Gln-D-Ser-D-Ile-D-Leu-D-Glu-D-Ala-D-Tyr-D-Ser-D-Gln-D-Asn-D-Gly-D-Trp-D-Ala-D-Asn-D-Arg-D-Arg-D-Ser-D-Gly-D-Gly-D-Lys-D-Arg-D-Pro-D-Pro-D-Pro-D-Arg-D-Arg-D-Arg-D-Gln-D-Arg-D-Arg-D-Lys-D-Lys-D-Arg-D-Gly-OH
CAS Number
2460055-10-9
Molecular Formula
C228H388N86O64
Molecular Weight
5358.05
1. Insulin Signaling
It has long been understood that FOXO proteins are important regulators of insulin signaling, but that they act downstream of the insulin itself as well as insulin-like growth factors. Research in animal models indicates that FOXO mediates that inhibitor effects of insulin and insulin-like growth factor on cell metabolism, growth, differentiation, oxidative stress, and more. Mutations in FOXO are connected to pathologic changes in insulin signaling and the development of metabolic disease as well as cancer. In diabetics, alterations of FOXO signaling leads to fasting hyperglycemia and hyperlipidemia[6]. The latter is one of the most concerning aspects of diabetes as it leads to many of the complications of the disease such as kidney damage, stroke, heart attack, impaired wound healing, and more. The ability to regulate FOXO signaling in diabetes could provide for more targeted, more effective methods of preventing some of the serious complications of the disease. It is unclear how FOXO4-DRI affects insulin signaling, but it is thought that the protein can improve downstream effects of insulin by reducing fasting blood sugar levels.
2. Heart Disease
Age is a risk factor for cardiovascular disease. This risk appears to be mediated by declines in proteasome activity in the heart. Proteasomes are responsible for removing oxidized proteins and other proteins that the cell has marked as “damaged” or dysfunctional. Research in rats shows that age is inversely correlated with proteasome activity and thus increases in levels of damaged proteins within the heart[7].
FOXO proteins mediate autophagy and proteasome activity. Increases in FOXO4 levels lead to increases in proteasome activity and thus decreased levels of oxidation and protein damage within specific tissue. It may be possible that FOXO4-DRI or a variant of it can be used to boost the heart’s natural housekeeping functions and thus reduce age-related changes in cardiovascular function[8].
3. Neurodegenerative Disease
Age-related changes in cognitive function have a complex etiology. Even relatively common diseases, like Alzheimer’s disease, are not fully understood by the medical community. There is some evidence, however, to support the notion that changes in proteasome activity can lead to or exacerbate underlying neurodegenerative conditions. It isn’t clear if impaired proteasome activity is a primary cause or secondary contributor to diseases like Alzheimer’s disease, but impairment of the systems has been found in Parkinson’s, Alzheimer’s, Huntington’s, and Prion disease. There is also impairment of proteasome function in amyotrophic lateral sclerosis (ALS or Lou Gehrig’s disease) [9].
It appears that FOXO proteins are modified in the central nervous system, a finding that has led researchers to explore the idea that exogenous FOXO protein may be useful in treating or preventing neurodegenerative disorders. At the very least, there is hope that FOXO4-DRI and other modified FOXO proteins may be useful in slowing the relentless progression of neurodegenerative disorders [10].
Summary
FOXO4-DRI has been clearly demonstrated to boost apoptosis in cells that have become senescent, leading to improved tissue function and better overall health in animal models. It remains to be seen just how extensive the effects of FOXO4-DRI are, but there is hope that the protein can unlock insight into age-related conditions like dementia, heart disease, and general loss of function caused by cell senescence.
COA
HPLC
MS
W. Liu, Y. Song, J. Wang, H. Xiao, Y. Zhang, and B. Luo, “Dysregulation of FOXO transcription factors in Epstein-Barr virus-associated gastric carcinoma,” Virus Res., p. 197808, Nov. 2019.
A. T.-Y. Chen et al., “Longevity Genes Revealed by Integrative Analysis of Isoform-Specific daf-16/FoxO Mutants of Caenorhabditis elegans,” Genetics, vol. 201, no. 2, pp. 613–629, Oct. 2015.
P. Krimpenfort and A. Berns, “Rejuvenation by Therapeutic Elimination of Senescent Cells,” Cell, vol. 169, no. 1, pp. 3–5, 23 2017.
“Senescence and aging: Causes, consequences, and therapeutic avenues | JCB.” [Online]. Available: http://jcb.rupress.org/content/217/1/65. [Accessed: 17-Nov-2019].
S. Lee and H. H. Dong, “FoxO integration of insulin signaling with glucose and lipid metabolism,” J. Endocrinol., vol. 233, no. 2, pp. R67–R79, 2017.
A.-L. Bulteau, L. I. Szweda, and B. Friguet, “Age-dependent declines in proteasome activity in the heart,” Arch. Biochem. Biophys., vol. 397, no. 2, pp. 298–304, Jan. 2002.
G. Murtaza, A. K. Khan, R. Rashid, S. Muneer, S. M. F. Hasan, and J. Chen, “FOXO Transcriptional Factors and Long-Term Living,” Oxid. Med. Cell. Longev., vol. 2017, 2017.
A. Ciechanover and P. Brundin, “The ubiquitin proteasome system in neurodegenerative diseases: sometimes the chicken, sometimes the egg,” Neuron, vol. 40, no. 2, pp. 427–446, Oct. 2003.
W. Hu et al., “Roles of forkhead box O (FoxO) transcription factors in neurodegenerative diseases: A panoramic view,” Prog. Neurobiol., vol. 181, p. 101645, Oct. 2019.
Article/Literature Citation Notes
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