This post is concerned with recent research focused on the impact of the FOXO (Forkhead) transcriptions factors on the health of hematopoietic stem cell pools in human bodies. As regular readers of this blog may know, I see stem cells as playing key roles in the aging process and I have recently added a new theory of aging to my Anti-Aging Firewalls Treatise, the Stem Cell Supply Chain Breakdown theory. In this blog post I briefly discuss how the FOXO genes have been seen to be related to longevity, review a few research findings relating FOXOs to stem cells, and speculate on what these could mean for resveratrol takers.
There are hundreds of publications related to the human FOXO transcription factors FKHR (FOXO1), FKHR-L1 (FOXO3a) and AFX (FOXO4). The molecular activities of these factors are fascinating but most of them are too complex to be discussed here. I mention only a few key findings:
· “FOXO transcription factors are at the interface of crucial cellular processes, orchestrating programs of gene expression that regulate apoptosis, cell-cycle progression, and oxidative stress(ref).” They play key roles in DNA repair, energy homeostasis, glucose metabolism, reactive oxygen species detoxification, cell cycle arrest, and cell death.
· It has been suspected for some time that the FOXO factors are implicated in the human aging process. “A homologue of FOXO1A, daf-16, has been associated with ageing in roundworms [ref], and overexpression of another homologue, dFOXO, in adult fat body of fruit flies increased longevity in females [ref](ref).” In fact, this FOXO signaling pathway was first identified in the nematode worm Caenorhabditis elegans where it was noted for its longevity impacts.
· A polymorphism of the FOXO3 gene is definitely associated with longevity in humans. It is found in most centenarians across a variety of ethnic groups around the world(ref)(ref)(ref).
· “Consistent with the notion that stress resistance is highly coupled with lifespan extension, activation of FOXO transcription factors in worms and flies increases longevity. Emerging evidence also suggests that FOXO factors play a tumor suppressor role in a variety of cancers. Thus, FOXO proteins translate environmental stimuli into changes in gene expression programs that may coordinate organismal longevity and tumor suppression(ref).
· The sirtuin SIRT1 regulates the FOXO genes. “The Sir2 deacetylase modulates organismal life-span in various species. However, the molecular mechanisms by which Sir2 increases longevity are largely unknown. We show that in mammalian cells, the Sir2 homolog SIRT1 appears to control the cellular response to stress by regulating the FOXO family of Forkhead transcription factors, a family of proteins that function as sensors of the insulin signaling pathway and as regulators of organismal longevity. SIRT1 and the FOXO transcription factor FOXO3 formed a complex in cells in response to oxidative stress, and SIRT1 deacetylated FOXO3 in vitro and within cells. SIRT1 had a dual effect on FOXO3 function: SIRT1 increased FOXO3’s ability to induce cell cycle arrest and resistance to oxidative stress but inhibited FOXO3’s ability to induce cell death(ref).”
· Resveratrol, used by some as an anti-aging supplement, activates SIRT1 and its longevity impacts are thought to be due to the actions of the FOXO factors as impacted by SIRT1(ref).
I have mentioned most of these facts before. They are listed here mainly for background.
The research relating FOXO to stem cells is encapsulated by the title of this research publication: “Foxo3a Is Essential for Maintenance of the Hematopoietic Stem Cell Pool.” See also “FoxO Transcription Factors and Stem Cell Homeostasis: Insights from the Hematopoietic System.” “Hematopoietic development is regulated by a dynamic balance between HSC (hematopoietic stem cell) self-renewal and differentiation to mature effector cells. The balance between self-renewal and differentiation is of critical importance: too little self-renewal or too much differentiation may jeopardize the ability to sustain hematopoiesis throughout life, whereas excessive self-renewal and/or aberrant differentiation may result in leukemogenesis. The regulation of HSC self-renewal is not fully understood, but recent studies have underscored the importance of cell cycle, apoptosis, and oxidative stress response in HSC homeostasis. Recent data indicate that FoxO family members play a critical role in these physiologic processes in the HSC compartment and thereby regulate maintenance and integrity of HSCs(ref).”
Maintenance of the stem cell pools health can be a very critical matter. “The researchers at Brigham and Women’s found that mice engineered to lack genes for the FoxO1, FoxO3, and FoxO4 molecules had serious blood abnormalities. Without the FoxO gene-regulating molecules, the rodents’ blood stem cells — master cells that give birth to working blood cells while also renewing themselves ¬– divided too fast and “burned out,” said Gary Gilliland, MD, PhD, who is senior co-author of the two papers with Ronald DePinho, MD, of Dana-Farber. “If we didn’t have these FoxO proteins to keep stem cells healthy, it is likely that we wouldn’t be able to live for more than a few months,” said Gilliland(ref).”
There may be a major implication regarding the action of resveratrol. It could be that some or all of resveratrol’s reported life-extending benefits are due to enhancing the proliferative and differentiating capabilities of pools of stem cells via activation of SIRT1 and FOXO3A signaling. It is difficult to say this for sure since FOXO also plays key roles in defense against cancers and in assuring antioxidant defense. There is growing reason to see aging in terms of Stem Cell Supply Chain Breakdown.