An important approach to retarding aging that I have not discussed explicitly so far is hormesis, challenging cells and body systems by mild stress resulting in them becoming stronger and resistant to aging(ref). The stress can be physical, chemical and even possibly psychological. Regular exercise is a familiar activity that produces hormetic effects. I can assure you that mild stress is involved because I just got off my treadmill and am still sweating a bit. And I expect this will help me live longer. Also, many of the supplements in the combined anti-aging regimen likely exercise some of their positive effects via hormesis. I review some of the science related to hormesis here, especially the roles of heat shock proteins and chaperones. And I discuss how the phyto-substances featured in my anti-aging firewalls work through hormesis.
The anti-aging effects of hormesis have been observed experimentally.
In the 2004 paper Slowing down aging from within: mechanistic aspects of anti-aging hormetic effects of mild heat stress on human cells, the authors report: “In a series of experimental studies, we have reported that repeated mild heat stress (RMHS) has anti-aging hormetic effects on growth and various cellular and biochemical characteristics of human skin fibroblasts undergoing aging in vitro. These beneficial effects of repeated challenge include the maintenance of stress protein profile, reduction in the accumulation of oxidatively and glycoxidatively damaged proteins, stimulation of the proteasomal activities for the degradation of abnormal proteins, improved cellular resistance to other stresses, and enhanced levels of cellular antioxidant ability. In order to elucidate the molecular mechanisms of hormetic effects of RMHS, we are now undertaking studies on signal transduction pathways, energy production and utilization kinetics, and the proteomic analysis of patterns of proteins synthesized and their posttranslational modifications in various types of human cells undergoing cellular aging in vitro.” The Danish authors of this paper also see hormesis as a possible systematic anti-aging intervention. “Human applications of hormesis include early intervention and modulation of the aging process to prevent or delay the onset of age-related conditions, such as sarcopenia, Alzheimer’s disease, Parkinson’s disease, cataracts and osteoporosis(ref).”
The 2009 paper Heat Stress and Hormetin-Induced Hormesis in Human Cells: Effects on Aging, Wound Healing, Angiogenesis, and Differentiation was generated by some of the same Danish authors and represents their continuing research. This paper confirms the earlier observations and goes on to say “RMHS (repeated mild heat stress ) given to human cells increased the basal levels of various chaperones, reduced the accumulation of damaged proteins, stimulated proteasomal activities, increased the cellular resistance to other stresses, enhanced the levels of various antioxidant enzymes, enhanced the activity and amounts of sodium-potassium pump, and increased the phosphorylation-mediated activities of various stress kinases. We have now observed novel hormetic effects of mild heat stress on improving the wound healing capacity of skin fibroblasts and on enhancing the angiogenic ability of endothelial cells. We have also tested potential hormetins, such as curcumin and rosmarinic acid in bringing about their beneficial effects in human cells by inducing stress response pathways involving heat shock proteins and hemeoxygenase HO-1. These data further support the view that mild stress-induced hormesis can be applied for the modulation, intervention and prevention of aging and age-related impairments.”
I have discussed curcumin repeatedly in my treatise and rosmarinic acid in the recent blog post with that name. The concepts that these substances work by “inducing stress response pathways involving heat shock proteins and hemeoxygenase HO-1” is an interesting one that I have not explored before.
Hormesis can operate through the activation of heat shock proteins
Heat shock proteins (HSPs) are produced by cells when the cells are exposed to elevated temperature or other stresses. Their role is to protect cells and tissues which they do by regulating important cellular functions when they are expressed due to stress. “Hsps are expressed in response to an array of stresses, including hyperthermia, oxygen radicals, heavy metals, ethanol, and amino acid analogues. In addition, the heat shock response is induced during clinically relevant situations such as ischemia/reperfusion and circulatory and hemorrhagic shock. All of the above stresses have in common that they disturb the tertiary structure of proteins and have adverse effects on cellular metabolism. Pretreatment of cells with a mild stress, sufficient to induce the expression of hsps, results in protection to subsequent insults. This phenomenon has been coined “stress tolerance” and is apparently caused by the resolubilization of proteins that were denatured during the stress(ref).” Discovered in 1974, a large literature has been built up about heat shock proteins which appear to be evolutionary conserved and observed in a wide variety of organisms ranging from bacteria to humans(ref). Many, but not all chaperone proteins are also HSPs, so in some discussions the terms “heat shock protein” and “chaperone protein” are incorrectly used interchangeably.
Hormesis theory of anti-aging
The hormesis theory of anti-aging is that by systematically introducing mild systematic stresses on body systems , heat shock proteins will be generated and molecular pathways will be activated that exercise protective effects on cells and consequently on entire organisms; the result will be delayed aging.
Examples on the level of entire organisms are calorie restriction(ref) and exercise. Hormesis is observed on multiple levels. For example, confronting mental challenges preserves memory and cognitive capability(ref)(ref)(ref). A study in Florida of 660 older people, aged aged 63 to 97, showed that people who kept driving were four to six times more likely to still be alive after a three-year period than their counterparts who stopped driving(ref). Another example may be Polygamy which helps men live 12% longer according to research studies(ref). One possibility is that polygamy extends life of men because “the challenge multiple wives pose requiring constant physical and mental activity.” I have written several times earlier on hormetic effects without using that name. See my blog entry Stress and longevity for a further discussion of how moderate stresses confer longevity.
Too much stress, stress that overwhelms the body’s defenses can of course be dangerous or lethal and excess or the wrong kind of stress can further the progress on some diseases like melanoma(ref). For many substances there is a response curve based on dose where there is a transition point beyond which the effect is no longer beneficial and is deleterious(ref).
Hormesis and dietary phytochemicals
The 2007 publication Dietary Factors, Hormesis and Health states “Some specific dietary components may also exert health benefits by inducing adaptive cellular stress responses. Indeed, recent findings suggest that several heavily studied phytochemicals exhibit biphasic dose responses on cells with low doses activating signaling pathways that result in increased expression of genes encoding cytoprotective proteins including antioxidant enzymes, protein chaperones, growth factors and mitochondrial proteins. Examples include: activation of the Nrf-2 – ARE pathway by sulforaphane and curcumin; activation of TRP ion channels by allicin and capsaicin; and activation of sirtuin-1 by resveratrol.”
The age-prolonging effects of phytochemicals, as pointed out in the 2008 publication Hormetic dietary phytochemicals. “One general mechanism of action of phytochemicals that is emerging from recent studies is that they activate adaptive cellular stress response pathways. From an evolutionary perspective, the noxious properties of such phytochemicals play an important role in dissuading insects and other pests from eating the plants. However at the subtoxic doses ingested by humans that consume the plants, the phytochemicals induce mild cellular stress responses. This phenomenon has been widely observed in biology and medicine, and has been described as ‘preconditioning’ or ‘hormesis.’ Hormetic pathways activated by phytochemicals may involve kinases and transcription factors that induce the expression of genes that encode antioxidant enzymes, protein chaperones, phase-2 enzymes, neurotrophic factors, and other cytoprotective proteins. Specific examples of such pathways include the sirtuin-FOXO pathway, the NF-kappaB pathway, and the Nrf-2/ARE pathway.”
Specifically, my blog post Nrf2 and cancer chemoprevention by phytochemicals discusses the signaling pathways involved in the hormetic process initiated by some phytochemicals , including the roles of the nuclear factor Nrf2 and the MAPK/ERK and PI3K/Akt pathways . I have discussed these pathways and the sirtuin-FOXO and NF-kappaB pathways before in this blog and in my treatise.
Hormesis and the anti-aging firewalls
I have already mentioned how several of the suggestions in my lifestyle firewall regimen, like exercise and keeping mentally and socially active, tend to be life-extending by creating hormetic effects.
Several supplements in my anti-aging firewalls supplement regimen have been shown in-vitro to act via activation of heat shock proteins and hormesis. The document Curcumin, a medicinal herbal compound capable of inducing the heat shock response, for example, concludes “Curcumin, a widely used medicinal compound, induces the heat shock response in vitro as measured by expression of heat shock protein 70. The mechanism of heat shock protein 70 induction depends on activation of heat shock factor-1. Examining known inhibitors of nuclear factor-KB for their ability to induce heat shock protein 70 may be a valid screening method to discover novel pharmacologic inducers of the heat shock response.” Thirty nine substances in my combined firewall regimen are known inhibitors of NF-kappaB and many if not most of these are likely to activate heat shock proteins.