Chapter 15: Rheumatoid Arthritis is an Thrifty Condition That Helps to Save Energy

Rheumatoid Arthritis Defined:

Rheumatoid arthritis is a long-term autoimmune disorder that primarily affects joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and hands are involved, with the same joints typically involved on both sides of the body. Symptoms include:   Pain or aching in more than one joint Stiffness in more than one joint Tenderness and swelling in more than one joint Fatigue or tiredness Weakness.

Summary

Epidemiological and comparative evidence can be taken to support the hypothesis that rheumatoid arthritis (RA) may be a thrifty adaptation that compels animals to minimize voluntary energy expenditure. The pain and inflammation underlying RA are framed here as constituting an evolved, protective mechanism that would have influenced animals to avoid exertion and maintain a sedentary lifestyle to minimize metabolic output and ultimately escape starvation. Arthritic discomfort is characterized here as a defensive, innate signal much like fatigue, fever, nausea, and reflexive pain. Like these, it is seen on a continuum varying between imperceptible encumbrance and debilitating disability. The fact that psychological stress can cause arthritic symptoms to flare up is taken to suggest that arthritis may be a predictive, adaptive response to severe stress allowing reductions in metabolism to follow adverse conditions or nutritional scarcity. The close associations between rheumatoid arthritis and the metabolic syndrome are also explored, along with potential ties to the “thrifty genotype” and “thrifty phenotype” phenomena. This hypothesis is examined in the contexts of evolutionary medicine, phenotypic plasticity, the stress response, and the bioenergetics of thrift. RA, its subclinical manifestations, and even other forms of arthritis may represent adaptations that promoted metabolic thrift during our evolutionary past.

Rheumatoid Arthritis and Natural Selection

The objective of this research is to analyze evidence suggesting that rheumatoid arthritis (RA) is an adaptive, thrifty trait that conditions animals to minimize extraneous physical activity. Unfortunately, in the current literature, the etiology and principal causes of RA are thought to be unknown due to the paucity of reliable generalizations regarding environmental contributors and genetic underpinnings (Sanchez-Pernaute et al., 2008; Vierboom et al., 2005). Also, the comparative data showing how arthritis presents in other animals is sparse and dense. Despite these hindrances, a valid evolutionary perspective should allow insight into how the disease develops. In this tradition, this chapter will postulate as to the evolutionary benefits of RA and perform a very general and exploratory review of the evidence that ties RA specifically, and arthritis in general, to metabolic thrift.

Rheumatoid arthritis (RA) is one of the most common immune-mediated inflammatory diseases (IMID) and is a major cause of disability worldwide. It is a complex autoimmune disease that primarily affects the synovial joints of the extremities and results in severe inflammation and the progressive destruction of cartilage and subchondral bone (Silman & Pearson, 2002). Symptoms of RA include pain and stiffness, which can impair mobility and restrict movement (Majithia & Geraci, 2007). Many different susceptibility genes, most of which may be unidentified, appear in different arrangements to produce a heterogeneous clinical picture. Recent molecular investigations show that slight perturbations in gene expression and epigenetic mechanisms can determine how, where, and when RA will manifest. The disease can start at any age; however, the average peak onset occurs between 25 and 55 (Vierboom et al., 2007). The disease is rare before age 15, but susceptibility increases after age 15 until 80 (Turesson et al., 2003).

Clearly, RA would have been exposed to evolutionary pressures in the ancestral past. It is thought that because modern hunter-gatherers live, on average, to age 55 (Blurton Jones et al., 1992; Hill et al., 1996) that our hunting and gathering ancestors would have lived nearly as long. This strongly suggests that our ancient ancestors would have experienced arthritis and preclinical arthritic symptoms well before they reached reproductive senescence. Like other disorders we have seen thus far because RA presents during the period of fertility, we can assume that natural selection had the opportunity to select against it. Yet, it exists today as a relatively prevalent disorder. This apparent inconsistency has been described as the arthritis paradox (Straub & Besedovsky, 2003). If the compensating benefits were uncovered, though, it would no longer be seen as an evolutionary enigma.

Straub and Besedovsky (2003) have applied evolutionary logic to the arthritis phenomenon and concluded that a thorough explanation is needed for the large human genetic predispositions for both RA and other chronic, disabling inflammatory diseases. They emphasize that because full-blown, clinical RA affects 1% of individuals around the globe (Grossman & Brahn, 1997) and because even juvenile RA is a relatively prevalent phenomenon, there must be some valid evolutionary explanation for it. The hygiene hypothesis is a popular evolutionary account for the phenomenon of auto-inflammatory disorders. This hypothesis contends that autoimmune disorders, including RA, exist because many modern hygienic precautions keep us from being exposed to pathogens that are integral to the proper formation of immunity and that this increases the likelihood that our immune systems will use their defenses against our tissues mistakenly. This is an interesting and perhaps fertile hypothesis, but nevertheless, there is very little supporting data in the case of RA, and it is known that individuals from cultures without modern hygienic practices still suffer from clinical RA. This paper takes a totally different approach hypothesizing that arthritis may represent an example of a metabolism reduction program or a “deprivation syndrome.” Arthritis is painful and limiting, yet it is easy to see how it could encourage a person or animal to conserve valuable energy.

The Hypothesis

Clearly, the fundamental symptoms of RA impose considerable constraints on mobility and behavioral activity. RA vastly decreases deliberative movement, cutting energy expenditure and minimizing the amount of food that must be consumed each day. It seems likely that the pain associated with RA intrudes upon an animal’s psychological life, influencing it to slow down and refrain from physically demanding activities. Moreover, the inflammation and physiological manifestations of RA have the ability, earlier in the disease, to induce pain for many years without damaging the joint beyond use. This would have influenced individuals with arthritis to engage in physically demanding activities only if necessary and to avoid them if possible. It seems clear that, even though RA is debilitating, it would not preclude crucial defensive or foraging behaviors unless it had progressed to an advanced degree.

Straub and Besedovsky (2003) hypothesize that early humans would have died before natural selection had the chance to remove the genes for RA from the human gene pool. They then go on to invoke antagonistic pleiotropy, assuming that genes that predispose to RA in later life have beneficial effects on growth and reproduction earlier in life. This is probably not the case, though, because RA is known to affect children and has a peak onset that begins at the early age of 25 (Vierboom et al., 2007). A slight twist on this logic leads us to speculate that perhaps subclinical and early RA produced adaptive benefits for foragers in their young adulthood, but then natural selection had no chance to curtail the debilitating effects in late life.

RA and its subclinical manifestations, as they present in young adulthood, are often relatively benign. Before RA leads to major disability in later life, it primarily acts to encumber “superfluous” movements and slow down the pace of life. The reduced physical activity in RA leads to muscle loss and skeletal muscle wasting (Ekdahl & Broman, 1992). Most individuals with RA experience involuntary loss of lean mass and a progressive increase in fat mass (Rall & Roubenoff, 2004). In times of starvation or nutritional scarcity, excess muscle mass is a significant metabolic burden, and thus RA may help economize by reducing muscle composition. Overall, individuals with RA are significantly more likely to be overweight and obese, as we will discuss later. In the ancestral past, when calories were lean, individuals with a slow metabolism would only very rarely have been overweight yet would have required fewer calories to survive.

An important criticism of the present hypothesis will point out that rheumatoid arthritis has a significant energy demand. The inflammatory process itself burns calories and can be responsible for raising metabolic rates during arthritic flare-ups. Studies have shown, however, that overall energy expenditure or basal metabolic rate is decreased in individuals with RA primarily because of low physical activity (Roubenoff et al., 2002). In rheumatoid arthritis, cytokines are released, and their thermogenic effect briefly increases the metabolic rate. However, as the disease becomes more advanced and leads to cachexia, energy expenditure drops well below normal (Pi-Sunyer, 2000). Muscle mass and lean body mass decrease significantly in most cases, and patients generally tend to exhibit significant increases in body fat due to a lower resting metabolism (Roubenoff et al., 2002). RA may be the most adaptive when in remission, a period where the joint and associated muscles are weakened, but the amount of inflammation is meager, allowing a lower basal metabolic rate.

It is possible that different forms of arthritis, outside of RA, confer thrifty advantages to the wide array of vertebrate species that are known to present with them. Consonant with this speculation, it might also be assumed that arthritis first evolved and became prevalent phylogenetically to serve such an adaptive purpose. For this reason, the natural variability in arthritis among living species may hold important clues for medical research. Genetic trends and patterns within and between species should prove informative, as should the relationship between prevalence and way of life. It is known that most mammals have shown evidence of arthritis, that it presents very conspicuously in apes, and that it appears to be related to specific foraging styles (Nunn et al., 2007). It will be interesting for future research to analyze the distribution of joint susceptibility to arthritis across animal groups.

We know that arthritis manifests differently in different animals, and we might expect to see this variation map onto the different ecological and muscular-skeletal demands of different species. Perhaps arthritis is more likely to present in less ecologically crucial joints. It is known that arthritis tends to affect larger, weight-bearing joints less. This certainly makes sense because severe arthritis in large joints would be more likely to compromise structural integrity and prove to be debilitating for the animal (Nunn et al., 2007). It would be interesting to see precisely how quadripedal apes develop arthritis in their wrists and knuckles because, based on the present hypothesis, it would be expected that apes exhibit a different pattern of arthritis that should be maximized to support their manner of locomotion, knuckle-walking.

For humans, the hands are often significantly affected by rheumatoid arthritis and osteoarthritis. The hands are mechanisms for concerted physical work. They are the modality through which humans carry, gesture, grab, play, pull, push, punch, tear, and strain. In humans, arthritis presents most frequently in the hands and wrists, and this may have dissuaded our ancestors from working excessively hard, rewarding them for inhibiting non-necessary movements.

RA that crops up before noticeable symptoms appear (presymptomatic and subclinical) is probably far more prevalent than RA itself and is known to create weakness, stiffness, and minor, diffuse discomfort in joints (Silman & Pearson, 2002). This suggests clinical arthritis may be on an extreme side of a phenotypic continuum of susceptibility to arthritic pain. It is conceivable that even very minimal, subclinical autoimmune inflammation of the synovial joints could have played a protective, thrifty role in evolution. It is even possible that natural selection positively selected the more subtle, subclinical manifestations of RA. As we will see, RA may be an especially relevant and helpful strategy for groups undergoing hardship, such as the starving, the stressed, pregnant women, and the elderly. 

Arthritis and Evolutionary Medicine

The costs of arthritis are well known and include limited mobility, occupational disability, and psychological stress/suffering. Its defensive manifestations may be hidden since our modern environment is very different from our ancestral environment.

So far, we have shown that RA is prevalent, heritable, and that susceptibility varies within a population. To determine if it could have had adaptive qualities that were positively selected in the past, it is essential to show how the trait’s purported benefits may have outweighed the costs (Nesse & Williams,1991).

Survival in the ancestral environment required adaptations to life-threatening scenarios. One of the most common of these would have been starvation, and conserving energy and resources would have been crucial. Hunger and its many neurobiological facets have been conceptualized as an adaptive signal ensuring an animal actively seeks food. Similarly, pain is an essential sensation that acts as a deterrent warning that damage is being done to the body. Hunger and pain are powerful examples demonstrating that suffering, though maladaptive in some contexts, proves to be far less costly than death (Nesse & Williams,1991). Similarly, nausea is an adaptive response that, through aversive conditioning, discourages animals from eating what made them sick.

We experience fatigue as a response to the need for rest. Fatigue and exhaustion indicate that further exertion could prove dangerous (Nesse & Williams, 1995). Additionally, fever is thought to reduce physical activity to speed up the recovery process. Interestingly, many people with arthritis report the sensation of chronic low-grade fever. It is interesting to note that pain, nausea, and fatigue are all aversive signals that encourage an animal to stop doing something. Arthritic pain may be a sensation that can signal an animal to stop moving or curtail an activity once basic needs have been satisfactorily met.

The Thrifty Genotype

We know that the Pleistocene era (roughly 2 million to 12 thousand years ago) was marked by frequent, prolonged dry spells (Ravello et al., 2004) and consequent widespread nutritional scarcity that continually threatened our ancestors (Reed, 1997; Bobe et al., 2002) Such unpredictability of food resources is widely thought to have seriously impacted the human genome (Wynn, 2004.) Genetic tendencies toward adiposity and insulin resistance would have allowed one’s metabolism to deal with low food availability in the ancestral environment. However, in modern times they are responsible for the high incidence of obesity and diabetes because of the availability of foods high in fats and sugars (Hales & Barker, 1992; 2001). A high genetic susceptibility towards obesity, diabetes, and the metabolic syndrome today would have constituted an adaptive, “thrifty genotype” in the ancestral past (Bateson et al., 2004; Wells, 2001).

There are many ties between the metabolic syndrome and rheumatoid arthritis. In fact, the prevalence of the metabolic syndrome in individuals with RA is among the highest of any known medical population. One study has shown that the metabolic syndrome was present in 42% of patients with long-standing RA, 31% with early RA, and only 11% of controls (Chung et al., 2008).

The Pima Indians of Sonora, Mexico, an arid desert region exposed to drought and famine for centuries, are another group with a very high prevalence of the metabolic syndrome. James Neel studied the Pima Indians and their genetic tendency towards adiposity and insulin resistance. He noted their proclivity for sedentary behavior and high prevalence of obesity and diabetes (Valencia et al., 1999). His experience influenced him to posit the thrifty genotype hypothesis and delineate the adaptive benefits of insulin resistance (Diamond, 2003).

A longitudinal epidemiological study conducted to estimate the prevalence of RA in the Pima Indians of Arizona showed that prevalence in Pima Indians was over ten times higher than in the American matched control samples (Del Puente et al., 1989). RA has also been shown to be more prevalent and more debilitating in the Pima and other groups of American Indians than in any other ethnic groups (Ferucci et al., 2005). These strong associations between the thrifty genotype and RA suggest that RA may play a role in bioenergetic thrift.

Epigenetics, Phenotypic Plasticity, and Arthritis

There is persuasive evidence supporting the idea that arthritis may be a predictive adaptive response to specific environmental cues that signify imminent ecological adversity. This section makes the case that arthritis may be a programmed reaction to difficult circumstances, such as starvation, stress, aging, and pregnancy. This hypothesis can be analyzed using the “predictive, adaptive response” paradigm, according to which adverse prenatal or postnatal events can cause an organism to express genes that would typically remain unexpressed, resulting in a phenotype that is suited for a stressful or deprived environment (Via & Lande, 1985). 

The characteristics of organisms ranging from plants to mammals have been shown to make plastic responses to environmental events, many of which are thought to represent defensive strategies (Pigliucci, 2001). As you know from previous chapters, these changes are made when environmental cues signal dormant genes to be expressed or expressed genes to become dormant, a process called epigenetics. The research in this area related to RA is still in its early stages, but arthritis has a large epigenetic component (Vanden et al., 2006) and is brought on and accelerated by specific environmental events (Sanchez-Pernaute et al., 2008).

Stress reliably accelerates arthritis progression and worsens symptoms (Walker et al., 1999). Psychological stress has been tied closely to onset and even to precede disease flare-ups (Gio-Fitman, 1996). Stress and stress hormones have also been shown to dramatically exacerbate pain in RA (Khasar et al., 2008). Also, stress-management interventions can produce powerful clinical benefits reducing helplessness and pain and increasing self-efficacy, coping, and health status (Parker et al., 1995). Stress is an internal signal indicating hunger or adversity, and it is known that animals can plastically respond to acute stress by canalizing a thrifty phenotype (Hales & Barker, 2001). If arthritis is a “predictive adaptive response” to stress, then it should be informative for researchers to focus heavily on the molecular pathways that tie stress to arthritic exacerbation.

High levels of stress are also associated with several different forms of widespread musculoskeletal pain (McBeth et al., 2007), including fibromyalgia (a disorder closely tied to arthritis) and chronic fatigue (Crofford, 1998), which reduce mobility and activity in a way that is very similar to RA (McBeth et al., 2005). There may potentially be many diseases that, like arthritis, fibromyalgia, and chronic fatigue, are not even classified as metabolic disorders but may have been naturally selected because of their indirect influence on metabolism and thrifty behavior.

Asthma may be another example. Asthma puts strict constraints on heavy exertion and may have been a biologically appropriate way for an animal’s selfish genes to teach it not to engage in vigorous or strenuous efforts. Asthma symptoms are exacerbated by chronic stress, and interestingly it is also closely tied to the thrifty phenotype phenomenon through a solid association with low birth weight (Villamor et al., 2009). 

Physical anthropological research has demonstrated that older adults cannot hunt or gather as productively as younger adults (Kaplan, 2003). This is due to decreased physical capacity for aerobic and anaerobic activity that often forces them to rely on handouts from younger foragers (Kaplan et al., 2000). Several researchers have inferred from gerontological data that the decline of athletic ability during aging (due to muscle loss (sarcopenia), lower growth hormone levels, lower testosterone levels, etc.) is, at least in part, a metabolism reduction program that must have benefitted aging individuals in the ancestral environment (Heininger, 2002; Zafon, 2006). The close association between arthritis and age (Vierboom et al., 2007) is an appropriate one given that arthritis may be yet another thrifty trait.

RA is common after the postpartum period (Mastorakos & Ilias, 2000) and may have served as a metabolism reduction program for mothers in the ancestral environment. Other defensive traits are also common in the postpartum period, such as fatigue and depression (Nesse, 1999). Randolph Nesse has postulated that since pregnant women would have needed to conserve calories to nurse their children, depression and fatigue may have been essential survival adaptations for new mothers. RA disease activity has been shown to increase significantly in a large proportion of women just days after delivery (de Man et al., 2008).

The ubiquity of the association between motherhood and RA seems to suggest that it reflects some epigenetic, adaptive process. Depression, in general, has been conceptualized as a deprivation syndrome, and interestingly, studies on depression (Frank et al., 1988) have shown that 40% of individuals from samples of the RA population met the diagnostic criteria for some form of clinical depression (Dickens et al., 2002). Nesse has also hypothesized that depression may be an adaptation that influences the organism to become more withdrawn and more risk averse, also possible advantages of RA. Furthermore, females are two to four times more likely to develop RA than males (Grossman & Brahn, 1997). This might reflect the increased selective pressure on males to retain mobility for the athletically demanding activity of hunting and the pressure on women to hoard calories for the metabolically demanding activity of pregnancy.

Children with juvenile RA, like adults, have been shown to be very psychologically hardy, and despite the immobility and pain of RA, surprisingly well-functioning in social, emotional, and behavioral measures, remarkably similar to control children without RA (Noll et al., 2000). This suggests that despite the accompanying physical limitations, RA does not necessarily cause a vast maladaptive burden on psychological well-being and hence may not have unduly hampered reproductive success due to psychological or motivational factors.

Discussion

This chapter has provided some preliminary evidence supporting the hypothesis that RA may be a physiological mechanism that discourages exertion and encourages the minimization of extraneous movement creating a sedentary behavioral strategy. Many evolutionary explanations are accused of being “adaptationist” and using the benefits of hindsight to explain known facts. Many of these explanations are disparagingly called “just so stories” because they are very difficult to prove one way or the other. It can be argued that RA and arthropathy generally have no adaptive qualities. However, the present hypothesis may be supported by a look at the “big picture.” A comprehensive perspective suggests that all prevalent disorders have a natural history, that many are adaptations, and that many adaptations represent attempts to budget metabolic energy. There are various examples of adaptations to fluctuating metabolic constraints throughout biology, and all organisms, from bacteria to plants to animals, have been shown to make them. Arthritis can be seen, in terms of bioenergetics, as analogous to any of an innumerable number of examples of mechanisms engineered by natural selection to restrict and set limits on metabolic output.

It is probable that endophenotypes and genetic patterns in RA, along with animal analogs (or homologs) of arthropathy can be analyzed in terms of the present theory to provide convergent evidence. It is even possible that eventually, genetic hypothesis testing could provide near incontrovertible proof for the present theory. Until then, comparing intron relative to exon mutations in susceptibility genes for arthritis, mapping gene linkages, scrutinizing genome-wide microarray analyses, and even looking for inter and intraspecific trends in genographic data may all provide further support.

It is a common observation that young mammals are extremely active; they run, jump, and play very energetically and seem only to be limited by their cardiovascular endurance. Middle-aged mammals are much more sedentary and must be strongly motivated if they are to exert themselves. There must be powerful physiological mechanisms being expressed with age to create these profound behavioral changes. Indeed some of these mechanisms must create uncomfortable psychological states to make animals more reluctant to move. It is common knowledge that many people report noticing increased reluctance to activity during their aging process and describe the feeling as very diffuse discomfort. This sensation may have many components, one of which may include the arthritis continuum.

After a brief review of the evidence, I feel comfortable concluding that evolution may have selected and maintained the genes responsible for the autoimmune assault on synovial joints. Hopefully, this chapter will influence researchers to use this paradigm to analyze other autoimmune and arthropathic disorders in the context of evolutionary causation. Surely osteoarthritis, crystal arthritis, attachment arthritis, and other forms of synovitis have evolutionary histories- ones that may even be associated with energy budgeting.

It is not expected that this paradigm will apply to every form of organic arthropathy or IMID. However, rheumatoid arthritis is identified here as a leading candidate, and researchers are encouraged to follow the lines of logic presented here to identify other candidates. Moreover, I hope that the hypothesis considered here- that the autoimmune inflammation, particular to RA, may be maintained in order to stimulate neurological pain systems- may ultimately be able to help arthritis researchers target the appropriate regulatory pathways to better treat the disease.

References

Bateson P, Barker D, Clutton-Brock T, Deb D, D’Udine B, Foley R, Gluckman P, Godfrey K, Kirkwood T, Mirazon Lahr M, McNamara J, Metcalfe N, Monaghan P, Spencer H, Sultan S. Developmental Plasticity and Human Health. Nature 2004;430:419-21.

Blurton Jones N, Smith L, O’Connell J, Hawkes K, Samuzora CL. 1992. Demography of the Hadza, an increasing and high density population of savanna foragers. Am J Phys Anthropol 89:159-181.

Bobe R, Behrensmeyer AK & Chapman RE. 2002. Faunal change, environmental variability and late Pliocene hominin evolution, J Hum Evol 42: 475–497.

Chris Dickens, PhD, Linda McGowan, PhD, David Clark-Carter, PhD and Francis Creed, MD Depression in Rheumatoid Arthritis: A Systematic Review of the Literature With Meta-Analysis Psychosomatic Medicine 64:52-60 (2002.

Chung CP, Oeser A, Solus JF, Avalos I, Gebretsadik T, Shintani A, Raggi P, Sokka T, Pincus T, Stein CM. Prevalence of the metabolic syndrome is increased in rheumatoid arthritis and is associated with coronary atherosclerosis. Atherosclerosis 196:756-763.

Crofford, L. J.; (1998). “The hypothalamic-pituitary-adrenal stress axis in fibromyalgia and chronic fatigue syndrome.” Zeitschrift für Rheumatologie 57 (2): S67-S71.

Del Puente A, Knowler WC, Pettitt DJ, Bennett PH. High incidence and prevalence of rheumatoid arthritis in Pima Indians. American Journal of Epidemiology 129, 6, 1170-1178.

DeWitt TJ, Scheiner SM. 2004. Phenotypic plasticity: Functional and conceptual approaches. Oxford University Press, Oxford.

De Man YA, Dolhain RJ, van de Geijn FE, Willemsen SP, Hazes JM. Disease activity of rheumatoid arthritis during pregnancy: results from a nationwide prospective study. Arthritis Rheum. Sep 15 2008;59(9):1241-8

Diamond J. (2003) The double puzzle of diabetes. Nature 423: 599-602

Ekdahl C & Broman G. 1992. Muscle strength, endurance and aerobic capacity in rheumatoid arthritis: a comparative study with health subjects. Annals of the Rheumatic Diseases. 51:35-40.

Ferucci ED, Templin DW, Lanier AP. Rheumatoid arthritis in American Indians and Alaska Natives: a review of the literature. Semin Arthritis Rheum. 2005 Feb;34(4):662-7.

Fox CW, Mousseau TA. 1998. Maternal effects as adaptations for transgenerational phenotypic plasticity (TPP). In: Mousseau TA, Fox CW, editors. Maternal Effects as Adaptations. Oxford: Oxford University Press; 1998. P. 159-77

Frank RG, Beck NC, Parker JC, Kashani JH, Elliott TR, Haut AE, Smith E, Atwood C, Brownlee-Duffeck M, Kay DR. Depression in rheumatoid arthritis. J Rheumatol. 1988 Jun;15(6):920-5.

Gio-Fitman J. The role of psychological stress in rheumatoid arthritis. Medsurg Nurs. 1996 Dec;5(6):422-6. Links

Grossman JM & Brahn E (1997). Rheumatoid arthritis: current clinical and research directions. Journal of Womens Health 6, 627-638.

Hales CN, Barker DJ. Type 2 (non-insulin-dependent) diabetes mellitus: the thrifty phenotype hypothesis. Diabetologia 1992; 35: 595-601.

Hales CN, Barker DJ. The thrifty phenotype hypothesis. Br Med Bull 2001; 60:5-20.

Heininger Kurt. Aging is a deprivation syndrome driven by a germ-soma conflict.Ageing Research Reviews 2002, 1:481-536.

Hill K, Hurtado AM. 1996. Ache life history: the ecology and demography of a foraging people. Hawthorne, NY: Aldine de Gruyter. And Howell N. 1979. Demography of the Dobe !Kung. New York: Academic Press.

Kaplan H, Hill K, Lancaster J, Hurtado AM. The evolution of intelligence and the human life history. Evol Anthrop 2000; 9:156-84.

Kaplan H, Lancaster J, Robson A. 2003. Embodied Capital and the Evolutionary Economics of the Human Life Span. Population and Development Review, Vol. 29.

Khasar SG, Burkham J, Dina OA, Brown AS, Bogen O, Alessandri-Haber N, Green PG, Reichling DB, Levine JD. Stress induces a switch of intracellular signaling in sensory neurons in a model of generalized pain. J Neurosci. 2008. 28(28):5721-30.

Majithia V, Geraci SA 2007. Rheumatoid arthritis: diagnosis and management. Am J Med. 120 (11): 936-9.

Mastorakos G, Ilias I. 2000. Maternal hypothalamic-pituitary-adrenal axis in pregnancy and the postpartum period. Postpartum-related disorders. Ann NY Acad Sci. 900:95-106.

McBeth J, Chiu YH, Silman AJ, Ray D, Morriss R, Dickens C, Gupta A, Macfarlane GJ. (2005). “Hypothalamic-pituitary-adrenal stress axis function and the relationship with chronic widespread pain and its antecedents”. Arthritis Res Ther. 7 (5): R992–R1000

McBeth J, Silman AJ, Gupta A, Chiu YH, Ray D, Morriss R, Dickens C, King Y, Macfarlane GJ. (2007). “Moderation of psychosocial risk factors through dysfunction of the hypothalamic-pituitary-adrenal stress axis in the onset of chronic widespread musculoskeletal pain: findings of a population-based prospective cohort study.”. Arthritis Rheum. 2007 Jan;56(1):360–71.. 56 (1): 360–71.

McGeer PL, McGeer EG. Alzheimer’s Disease: Arthritis of the Brain? Drug News and Perspectives, , 1995 – JR PROUS SA

Nesse R, Williams G. Why We Get Sick. New York: Random House; 1995.

Nesse R, Williams G. Evolution and the origins of disease. Sci Am 1998; 279: 58-65.

Nesse, R. What Darwinian medicine offers psychiatry. In: Trevathan W, Smith E, McKenna J, editors. Evolutionary Medicine. Oxford: Oxford University Press; 1999.

Neel JV. 1962.  Diabetes mellitus: a ‘thrifty’ genotype rendered detrimental by ‘progress’? Am. J. Hum. Genet. 14, 353-362.

Noll RB, Kozlowski K, Gerhardt C, Vannatta K, Taylor J, Passo M. Social, emotional, and behavioral functioning of children with rheumatoid arthritis. Arthritis Rheum. 2000 43 (6): 1387-96.

Nunn CL, Rothschild B, Gittleman JL. Why are some species more commonly afflicted by arthritis than others? A comparative study of spondyloarthropathy in primates and carnivores. J Evol Biol. 2007 Mar;20(2):460-70.

Parker JC, Smarr KL, Buckelew SP, Stucky-Ropp RC, Hewett JE, Johnson JC, Wright GE, Irvin WS, Walker SE. Effects of stress management on clinical outcomes in rheumatoid arthritis. Arthritis Rheum. 1995 Dec;38(12):1807-18. Links

Pigliucci M. 2001. Phenotypic Plasticity: Beyond Nature and Nurture. Johns Hopkins University Press, Baltimore.

Pi-Sunyer FX. 2000. Overnutrition and undernutrition as modifiers of metabolic processes in disease states The American Journal of Clinical Nutrition. 72: 533S-537S.

Rall LC, Roubenoff R. 2004. Rheumatoid cachexia: metabolic abnormalities, mechanisms and interventions. Rheumatology 43:1219-23.

Ravelo AC, Andreasen DH, Lyle M, Lyle AO and Wara MW. 2004. Regional climate shifts caused by gradual global cooling in the Pliocene epoch, Nature 429: 263–267.

Reed KE. 1997. Early hominid evolution and ecological change through the African Plio–Pleistocene, J Hum Evol 32: 289–322.

Roubenoff R, Walsmith J, Lundgren N, Snydman L, Dolnikowski GJ & Roberts S. 2002. Low physical activity reduces total energy expenditure in women with rheumatoid arthritis: implications for dietary intake recommendations. Am J Clin Nutr 76:774-9.

Sanchez-Pernaute O, Ospelt C, Neidhart M, Gay S. Epigenetic clues to rheumatoid arthritis. Journal of Autoimmunity. 2008 30 12-20.

Smyth, J., Stone, A., Hurewitz, A., Kaell, A. (1999) Effects of writing about stressful experiences on symptom reduction in patients with asthma or rheumatoid arthritis: A randomized trial. JAMA, 281, 1304-1309.

Silman AJ, Pearson JE.Epidemiology and genetics of rheumatoid arthritis. Arthritis Res. 2002;4 Suppl 3:S265-72.

Straub RH, Besedovsky HO. 2003. Integrated evolutionary, immunological, and neuroendocrinic framework for the pathogenesis of chronic disabling inflammatory diseases. The FASEB Journal. 17: 2176-2183.

Traut EF, Thrift CB.Obesity in arthritis: related factors: dietary therapy.

J Am Geriatr Soc. 1969 Jul;17(7):710-7.

Turesson C, O’Fallon WM, Crowson CS, Gabriel SE, Matteson EL. 2003. Extra-articular disease manifestations in rheumatoid arthritis: incidence trends and risk factors over 46 years. Ann Rheum Dis 62 (8): 722-7.

Valencia M, Bennett P, Ravussin E, Esparza J, Fox C, Schulz L. The Pima Indians in Sonora, Mexico. Nutr Rev 1999; 57(5 Pt 2):S55-57.

Vanden BW, Ndlovu MN, Hoya-Arias R, Dijsselbloem N, Gerlo S, Haegeman G. Keeping up NF-kappa B appearances: epigenetic control of immunity or inflammation-triggered epigenetics. Biochem Pharmacol 2006; 72:1114-31.

Via S, Lande R. Genotype-Environment Interaction and the Evolution of Phenotypic Plasticity. Evolution 1985; 39(3):505-22.

Vierboom MP, Jonker M, Bontrop RE, ‘t Hart B. Modeling human arthritic diseases in nonhuman primates. Arthritis Res Ther. 2005;7(4):145-54.

Villamor, E., Iliadou, A., Cnattingius, S. (2009). Is the Association Between Low Birth Weight and Asthma Independent of Genetic and Shared Environmental Factors?. Am J Epidemiol 169: 1337-1343

Walker JG, Littlejohn GO, McMurray NE and Cutolo M.  Stress system response and rheumatoid arthritis: a multilevel approach. Rheumatology 1999; 38: 1050-1057

Williams G. Nesse R. The Dawn of Darwinian Medicine. Q Rev Biol 1991;66:1-22.

Williams DR. 1993. Epidemiological and geographic factors in diabetes. Eye. 7(2): 202-4.

Wells J. The thrifty phenotype hypothesis: thrifty offspring or thrifty mother? J Theor Biol 2003; 7:221(1):143-61.

Zafon, C. Spend less, live longer. The “thrifty aged” hypothesis.  Medical Hypotheses 2006, 67:15-20.