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Published in final edited form as: Aging Cell. 2010 Apr 23;9(4):519–526. doi: 10.1111/j.1474-9726.2010.00578.x

Cell resilience in species lifespans: a link to inflammation?

CE Finch *,#, TE Morgan *, VD Longo *, JP de Magalhaes +
PMCID: PMC2952360  NIHMSID: NIHMS200282  PMID: 20415721

Abstract

Species differences in lifespan have been attributed to cellular survival during various stressors, designated here as ‘cell resilience’. In primary fibroblast cultures, cell resilience during exposure to free radicals, hypoglycemia, hyperthermia, and various toxins has shown generally consistent correlations with the species characteristic lifespans of birds and mammals. However, the mechanistic links of cell resilience in fibroblast cultures to different species lifespans are poorly understood. We propose that certain experimental stressors are relevant to somatic damage in vivo during inflammatory responses of innate immunity, particularly, resistance to ROS, low glucose, and hyperthermia. According to this hypothesis, somatic cell resilience determines species' differences in longevity during repeated infections and traumatic injuries in the natural environment. Infections and injury expose local fibroblasts and other cells to ROS generated by macrophages and to local temperature elevations. Systemically, acute phase immune reactions cause hypoglycemia and hyperthermia. We propose that cell resilience to somatic stressors incurred in inflammation is important in the evolution of longevity and that longer-lived species are specifically more resistant to immune-related stressors. This hypothesis further specifies Kirkwood's disposable soma theory. We suggest expanding the battery of stressors and markers used for comparative studies to additional cell types and additional parameters relevant to host defense and to their ecological specificities.

Introduction

We propose the unifying hypothesis that species differences in fibroblast resilience to stressors is related to species lifespans by mechanisms of innate immunity in host defense. Primary fibroblast cultures are widely used to evaluate correlation to species lifespans for cell resilience to various stressors, including reactive oxygen species (ROS), hyperthermia, and hypoglycemia, as summarized in Table 1. These studies generally show positive correlations of species lifespan with short-term in vitro fibroblast survival and repair capacity. However, it is unclear how cell resilience to diverse stressors is related to aging and to causes of adult mortality.

Table.

Fibroblast Resilience Correlations with Species Longevity in Birds and Mammals (This survey was restricted to findings verified in separate reports)

Endpoint Species, ranked by
lifespan		 Lifespan ,y Correlation Citation
ROS exposure
LD90:H2O2 hamster, rat, marmoset,
rabbit, sheep, pig, cow,
human		 3 – 100 Positive Kapahi et al 1999
LD50:H2O2 mouse, rat, squirrel,
porcupine, beaver, bat		 3 – 34 Positive Harper et al 2007
LD50:H2O2, paraquat mouse, Snell dwarf
mouse		 2 –4 Salmon et al 2005;
Leiser et al 2006
LD50: paraquat mouse, naked-mole rat 3 – 28 Positive Salmon et al 2008
Hyperthermia
LD50 mouse, rat, squirrel,
porcupine, beaver, bat		 3 – 34 Positive Harper et al 2007
mouse, naked-mole rat 3 – 28 Positive Salmon et al 2008
Hypoglycemia
ED50 mouse, naked-mole rat 3 – 28 Positive Salmon et al 2008
mouse, Snell dwarf 2 – 4 Positive Leiser et al 2006
mouse, rat, squirrel,
porcupine, beaver		 3 – 24 Positive Harper et al 2007
H2O2 & O2
production
ED50 mouse, rat, rabbit, pig,
cow		 2 – 30 Inverse Sohal et al 1989;
1990
mouse, hamster, rat
guinea pig, rabbit, pig,
cow		 3 – 30 Inverse Ku et al 1993
mouse, rat, quail, guinea
pig, naked-mole rat, ox,
pigeon, bat, baboon		 3 – 38 Inverse Lambert et al 2007;
Barja et al 1994;
Ku & Sohal 1993
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Not shown: UV-induced “long-patch DNA excision repair” in fibroblast cultures, assayed by [3H]-thymidine incorporation, for which Hart and Setlow (1974) showed correlations with lifespan in 7 species including humans. Subsequent studies gave mixed outcomes: inverse correlations with lifespan were also found by a BrdU photolysis assay (Hart et al. 1979; Francis et al. 1981), while others did not find any correlation of UV-induced DNA repair synthesis with lifespan (Kato et al. 1980). Confounds include changes in DNA repair capacity during early stage passage of cells, and effects of the hydroxyurea used to suppress semi-conservative DNA replication (Francis et al. 1981).

The ROS stressors of Table 1 were historically guided by Harman's free radical theory of aging that ROS damage and oxidative stress are the major causes of age-related dysfunction and disease. Clearly, the main causes of mortality during later aging in protected populations of humans and domestic animals involve oxidative damage, e.g. atherosclerosis, neoplasia, diabetes, obesity, and neurodegeneration. However, in natural populations, predation, infections and traumatic injury are the major causes of mortality across all ages. For example, in feral chimpanzees, infections caused the majority (67%) of adult deaths (Williams et al 2008; Goodall, 1986, Finch 2010). Until recently, infections also caused most deaths across all ages in historical European populations (Preston, 1976), and in hunter-gatherers with limited access to effective medicine (Hawkes et al 2009; Finch, 2010). Although there is little documentation of older age-specific pathology in natural populations of shorter lived species, it seems unlikely that the majority of adults survived long-enough to incur chronic arterial and brain diseases of human aging associated with inflammation and oxidative damage.

Prior work on comparative stress resistance was largely focused on the need for longer-lived animals to limit oxidative and other damage. This focus neglected the possibility that a significant portion of damage is caused by infection and infection-related tissue responses. We argued that cell responses to ROS, hyperthermia, and hypoglycemia (Table 1) are highly relevant to host somatic cell damage during acute infections and traumatic tissue injury, as well as chronic localized inflammation. Specifically, cell resilience to ROS, heat stress, and low glucose are fundamental in the acute phase inflammatory responses of innate immunity, which involves ROS production by macrophages, hyperthermia (fever) and hypoglycemia. Thus, tissue fibroblasts and other cells are exposed as by-standers to similar stressors causing oxidative damage that are used for comparative experimental gerontology. Oxidative damage during inflammation, as a generalized mechanism in aging, is also recognized in Kirkwood's disposable soma theory of aging which posits the importance of trade-offs between allocation of energy for reproduction and somatic repair of diverse molecular damage (Kirkwood, 2005; Drenos and Kirkwood, 2005). Lastly, we suggest additional stressors and measures of cell resilience and criteria for ecological relevance to species comparisons.

Acute phase responses of innate immunity

The acute phase response of innate immunity enables short-term host defenses to transmissible pathogens and wounds. Subsequent survival is enhanced by adaptive immune responses by B- and T cells to antigens of the invading pathogens. Infections and wounds produce local and systemic responses evolved for efficient tissue repair and protection from septic infections. The complex processes of inflammation are still aptly represented in Celsus' classic aphorism: rubor et tumor cum calore et dolore (redness and swelling with heat and pain). Many acute phase responses also persist in the chronic inflammation associated with diseases of human aging.

Inflammation causes oxidative stress and DNA damage

Free radicals as described in the Harman theory are also fundamental to host defense. Microbial pathogens can activate blood macrophages and neutrophils to produce the respiratory burst through NADPH oxidase, which generates superoxide (O2−) and enhances phagocytosis. In neutrophils, bacterial killing occurs intracellularly in phagocytic vacuoles through pH alterations driven by NADPH oxidase, rather than by ROS (Segal 2005). Other ROS originating from superoxide include the hydroxyl radical (HO•) generated from H202 and peroxynitrite (ONOO−) and O2−. Tissue injury rapidly induces ROS from resident local cells and recruited leukocytes (Sen and Roy 2008). In the zebrafish larval model of sterile wounding, H2O2 from epithelial cells recruits leukocytes to the wound margin (Niethammer et al 2009).

ROS produced during host defense can cause oxidative damage to bystander cells and extracellular molecules. In the two stage model of oncogenesis, chronic inflammation is considered a tumor promoter (Coussens and Werb 2002). A leading example of ROS damage from inflammation is associated with gastric cancers, the second ranked cause of death among malignancies worldwide (Herrera et al 2005; WHO, 2009). A major cause of gastric cancer is chronic infection by Helicobacter pylori: about 15% of carriers develop peptic ulcers, with 1% progressing to cancer (Helicobacter and Cancer Collaborative Group, 2001). A major oncogenic pathway involves localized inflammatory cell responses to extracellular H. pylori. Infiltrating macrophages and neutrophils produce ROS that damages DNA in adjacent epithelial cells (8-OHdG) (Farinati et al 2003). Concurrently, shortening of telomere DNA is associated with mucosal cell proliferation (Kuniyasu et al 2003). Anti-inflammatory NSAIDs which inhibit COX-2 greatly reduced gastric cancer in human populations (Wang et al 2003). Crohn's disease and other idiopathic intestinal inflammatory disorders that are independent of H. pylori also increase the risk of gastric cancer (Itzkowitz and Yio, 2004). By-stander effects of inflammation causing oxidative stress and DNA damage extend to many other inflammatory conditions (Meira et al 2008; Kawanishi et al 2006; Fukata and Abreu, 2008). Thus, the comparative studies of fibroblast resilience (Table 1) may be considered as models for ROS by-stander damage during inflammation.

Selection for antimicrobial hyperthermia leads to thermotolerant fibroblasts

Fever is a key part of host defense, evolved to inhibit growth of microbial pathogens above their optimum temperature; even poilikotherms develop fever (Hasday et al 2000; Nesse and Williams 1996). However, hyperthermia can induce cell death (e.g. Bettaieb and Averill-Bates, 2008) through caspases-3 and -9 (Nagarsekar et al 2008). There is overlap of febrile heat-induced apoptosis with pyroptosis, a new type of cell death during inflammation that is caspase-1 dependent (Bergsbaken et al 2009).

Besides systemic hyperthermia, it is well documented, but less known, that local inflammation also increases local temperature, true to Celsus' aphorism. The best understood example is the hotspots in advanced atherosclerotic plaques, up to 3 °C above the adjacent arterial surfaces and in correlation to local macrophage density (Madjid et al 2002; Tan and Lip 2008; Toutouzas et al 2007). Local hyperthermia is produced by induction of UCP2, which uncouples mitochondrial ATP production from respiration, thereby generating radiant energy (Van De Parre et al. 2008). We suggest that local hyperthermia may be adaptive by inhibiting local bacteria that are associated with damaged vascular tissue. Chlamydia pneumoniae, among other common bacteria, is detected in atherosclerotic plaques and is debated as a risk indicator of vascular events (Di Pietro et al 2009; Stassen et al 2008; Kalayogku et al 2000). These mechanisms may extend to local skin hyperthermia observed during inflammation from bone fractures in hands and feet (Huygen et al 2004). Because fibroblasts express UCP2 (Mori et al 2008), we suggest that UCP2 induction and thermogenesis be included in species comparisons. Other markers induced by hyperthermia could include the level of cell ROS (Flanagan et al 1998) and SOD1 and SOD2 activity which is associated with cellular thermotolerance (Loven et al 1985; Hoshida et al 2002; Yamashita et al 2000).

Hypoglycemia and cellular resistance

Hypoglycemia during the acute phase of innate immunity, e.g. 3-6 hours after LPS injection in mice (Oguri et al 2002; Ali et al 2008; Cryer et al 2009) is understood as a bacteriostatic mechanism. In comparative studies (Table 1), fibroblasts from long-lived dwarf mice showed enhanced resistance to glucose deprivation-induced changes in a metabolic marker (WST-1 reduction), which is positively correlated with resistance against cytotoxic agents, such as hydrogen peroxide (Leiser et al 2006). The level of glucose starvation in these studies (0.1- 0.4 mg/ml) was in the low clinical range of transient hypoglycemia that disturbs human cognition and behavior (<0.50 mg/ml, or <50 mg/dL, Cryer 2007; Cryer et al 2009).

Acute phase resilience hypothesis and relevance of fibroblasts

We propose that cell resilience to oxidative damage from immune-related stressors is a critical component of longevity systems. Infections occur from ingestion and inhalation of transmissible viral and bacterial pathogens and ectoparasites. The importance of the infectious-inflammatory load to lifespan is shown by the increased lifespans of lab rodents from husbandry improvements which minimized chronic lung diseases, ectoparasites, and other endemic infections: for C57BL/6J mice at Jackson Labs, lifespans increased >50% from 1957 (17 mo) to 1970 (28 mo) (Finch 2007, p 137). Fibroblasts, as the main test cell in species comparisons (Table 1), are relevant to the importance of the skin in the Darwinian world. Skin fibroblasts are ubiquitously subject to chronic inflammation from ectoparasites and microbial fauna, and from wounds incurred during fighting or from aggressive social grooming (Takahashi and ori, 1982; Litvin et al 2007). The very long-lived naked mole rat incurs deep bites during intracolony aggression that pierce internal organs and are occasional fatal (Lacey et al. 1991; Clarkes and Faulkes, 2001; Chris Clarke, pers. comm.). Abscesses associated with bite wounds contain Pasteurella sp. and Haemophilus sp. (Artwohl et al 2002). The resilience of long-lived naked-mole rats to repeated wounding supports the disposable soma hypothesis (Kirkwood 2005) that selection for somatic cell resilience can retard aging.

Skin wounding stimulated responses remove necrotic debris and protect against infection that employ many innate immune system genes; fibroblasts may be stimulated to proliferate as well as undergo apoptosis (Fujiwara et al 2007; Santiago et al 2004). Wounding induces H2O2 production by epithelial cells that appear to guide the influx of leukocytes (Niethammer et al 2009), as noted above. The induction of SOD-1 and -2 and catalase (Steiling et al 1999; Schäfer and Werner 2008) is associated with the clearance of H2O2 and other ROS, which can impair wound repair (Wasserbauer et al 2008; Wilgus et al. 2005). Although fibroblast monolayers can be used as a wounding model, we are not aware of comparative studies related to species lifespans.

Other cells besides fibroblasts show inverse relationships of damage to lifespan. Aortic endothelial cells exposed to oxidant stress (hyperglycemia) showed more inflammatory gene induction in lab mice (C57BL/6) than the longer-lived deermouse (Peromyscus leucopus) (Labinskyy et al 2009). Similarly, less mitochondrial ROS was generated by P. leucopus aortic cells than by those from lab mice, consistent with other comparisons (Table 1). These findings of inverse relationships of species lifespans with both mitochondrial ROS and cell vulnerability to ROS in arterial tissues is consistent with fibroblast comparisons and give a basis for expanding the range of somatic cell types in comparative studies. Mucosal epithelial cells merit consideration in future species comparisons for their critical role in enteric and oral defenses.

Genomic comparisons of immune and cell death gene sequences

There is a major gap in understanding how the species differences in fibroblast phenotypes are related to genomic differences in terms of DNA sequence and gene expression. At the level of coding sequence, immune response genes show many relevant species differences; there are indications of lineage-specific innovation in mammals that would attenuate innate immune responses in longer-lived species (Wang et al 2006). Positive selection is well documented for immune response genes from codon ratio statistics for synonymous vs non-synonymous mutations (Nielsen et al 2005). Species differences in genes related to apoptosis comprise a considerable fraction of genes under positive selection since humans diverged from chimpanzees (Nielsen et al 2005).

Besides codon changes, there are many species differences in gene deletions and changes in expression profiles. The human and chimpanzee genomes show extensive gene deletions (Olson 1999; Wang et al 2006), many of which are associated with inflammatory responses, illustrated by examples relevant to immune function. Chimpanzees have deletions of ICEBERG, IL1F7, and IL1F8, which are on a pathway inhibiting expression of caspase-1 (Osborn et al 2005); these deletions could increase responses to LPS-induced IL-1 (Humke et al 2000). Humans differ from great apes in the absence of N-glycolylneuraminic acid (Neu5Gc) (Varki 2009) due to inactivation of CMAH, which enzymatically converts Neu5Ac to Neu5Gc. The inactivation of CMAH before 0.5 million years ago has implications for human-specific pathogens that target Neu5Ac: the chimpanzee malarial parasite binds Neu5Gc during erythrocyte invasion, while the human P. falciparum binds Neu5Ac. A comparison of humans and chimpanzees showed that genes associated with inflammatory responses and cell proliferation are more likely to show gene loss or gain, e.g. APOL1 which is only present in humans and mediates trypanosome resistance (Perry et al 2008).

Expression profiling of fibroblasts from different species is relatively undeveloped. We propose that gene expression comparisons across species with diverse lifespans may reveal genes involved in aging-related phenotypes. Species-specific cellular responses to stress and inflammation, in particular, may contribute to the evolution of longevity. Next-generation sequencing technologies that allow deep RNA sequencing that is more sensitive for expression profiling than traditional microarrays should be used (de Magalhaes et al 2010). Gene expression profiling of these cellular responses across rodents may identify genes and pathways that evolved unique roles in long-lived rodents and may contribute to their longevity. For example, rodent-human comparisons show differences in a DNA repair gene of relevance to ROS in the fibroblast model: the UV-damage DNA-binding protein (UV-DDB). Its much lower expression in mouse and hamster epidermal cells is consistent with deficits in global genome repair, relative to humans. Ectopic expression of DDB2 increased DNA repair in mouse fibroblasts and reduced UV-induced skin cancer in vivo (Alekseev et al 2005). We anticipate future studies to reveal additional species-specific differences in gene expression patterns that associate with longevity using new transcriptional profiling technologies.

For human-primate comparisons, the most detailed study may be the comparison of fibroblasts from adult human, bonobo, chimpanzee and gorilla by Affymetrix GENECHIP 5.0, with confirmation of select changes by Northern blots (Karaman et al 2003): of the 10,000 genes discriminated, about 1% showed ≥ 2-fold species differences including various associations with host defense: humans had higher expression of HLA-E, MICA, SDF1, and TGFβ1, but much lower expression of glypican 3, a heparin-sulfate proteoglycan. Another gene with direct links to immune function is the very low expression of the glycoprotein siglec-5 in human T cells, which is a factor in the much greater immune reactivity of human vs chimpanzee CD4 T cells, as shown by expression manipulation (Nguyen et al 2006). Of relevance to the evolution of cancer, the erbB proto-oncogene had higher expression in humans and two great apes vs several shorter-lived primates, while myc, ras-K and src did not differ (Nakamura and Hart, 1987).

None of these genes have been considered in the context of fibroblast resilience in species comparisons. These differences suggest a major evolutionary change in immune responses that are part of the biology of human longevity. It seems clear that no single assay can address the multiple facets of species differences, irrespective of microevolution of immune responses.

Somatic damage from inflammation is relevant to the disposable soma theory of aging according to which longevity is determined by the rate of accumulating somatic cell damage, which is offset by the level of energy allocation for repair and regeneration (Kirkwood 2005). Thus a short-lived mouse with ten progeny per mating will invest less in repair to oxidative damage than a long-lived chimpanzee with singleton births at 5 or more year intervals. This can be easily observed in unicellular organisms such as bacteria or yeast, which are much more resistant to multiple stresses after entering a non-reproductive phase (post-diauxid and stationary phases). The genomic basis of these species differences could be resolved by RNA profiling and DNA sequence comparisons. We anticipate that species differences in genes that protect against inflammatory damage and mediate repair will provide clues about repair and regeneration mechanisms in long-lived species that may explain the evolution of longevity.

Phylogenetic and ecological issues

The study of Kapahi et al (1999) was a benchmark by its inclusion of mammalian species from four taxonomic orders including humans. Studies of rodents with 8 species have generally confirmed the cell resilience-lifespan relationships (Harper et al 2007). Recent studies of species for in vitro comparisons have expanded the range of lifespans represented within a taxon. Inclusion of the extraordinarily long-lived naked mole rat (Heterocephalus glaber, lifespan >28 years) now gives a 7-fold range of lifespans, relative to lab rodents (Gorbunova et al 2008; Buffenstein 2008). Except for Heterocephalus glaber, the other species of this study are terrestrial. The inclusion of mole-rats raises new issues about the ecological relevance of experimental stressors: UV irradiation would not seem relevant to mole rats which have avoided sunlight for millions of years. Other ecophysiological adaptations may be important to experimental design. H. glaber lives entirely in long underground burrows, a niche occupied with other bathyergids for at least 20 million years (Early Miocene) (Nevo et al 1999). H. glaber has a low core temperature <34 °C and is considered close to poikilothermic (Buffenstein and Yahav, 1991). Nonetheless, fever with elevated core temperature can arise during innate immune activation (R. Buffenstein, pers. comm.). The low core temperature introduces a species-specific factor in culture conditions.

These major ecological differences from terrestrial rodents could be a factor in several anomalies. H. glaber fibroblasts are more sensitive to H2O2, UV, rotenone, and low glucose, while mouse did not differ from two mole-rats in ROS production by heart mitochondria (Lambert et al 2007) or levels of hepatic antioxidants SOD, catalase, and glutathione (Andziak and Buffenstein 2006). Moreover, in vivo the H. glaber had a higher load of oxidized lipids and proteins than mouse (Andziak et al 2006). The greater sensitivity of Heterocephalus lipids to oxidative damage H2O2 was considered “…provocative, because it does not support most models of oxidative stress and longevity” (Salmon et al 2008). However, H glaber has a very different habitat than the other rodents: the gas composition in its long narrow tunnels has very low pO2 (6%, hypoxia) and high pCO2 (10%, hypercapnia), which would kill most rodents (van Aardt et al 2007). Corresponding adaptations include hemoglobin with higher oxygen affinity and altered acid-base regulation (greater Bohr effect) (Johansen et al 1976; van Aardt et al 2007), which we suggest may extend to redox sensitivity of other biochemical systems mediating stress responses. Other rodents with lifespans of 20 years include beavers, porcupines, and squirrels (Gorbunova et al 2008; Austad 2009); other mole-rats may be shorter lived (Ansell's mole-rat, 21 y; Cape mole-rat, 11 y), but the small numbers observed preclude firm conclusions (http://genomics.senescence.info/species/).

Suggestions for future studies

Because the acute phase response exposes cells to both hyperthermia and hypoglycemia, future comparisons could consider heat shock responses (e.g. HSP70-1,2), the mitochondrial UCP2 which generates local hyperthermia, and glucose regulatory and transport proteins (e.g. Grp58, GLUT-4). Combinations of heat and low glucose should be examined by deep RNA profiling. We postulate that lifespans will scale with somatic cell resilience to combinations of stressors experienced during host defense. Bacterial endotoxins will also be useful as probes. The LPS endotoxin of common Gram-negative infections induces inflammatory gene induction in fibroblasts (Perfetto et al 2003; Warner et al 2004). The LPS induction of SOD-2 mRNA (Visner et al 1990) enhanced resistance to H2O2 (Röhl et al 2008). Further insights are anticipated from deep RNA profiling in basal and stressed cells. In parallel with ongoing rodent studies, we encourage further comparison of human cells with great apes and other anthropoids for which expression data are very limited.

Another consideration is allelic variation in the human cells used for comparisons, which so far as we know have not been considered in species comparisons. For example, caspase 12 varies between human populations in the level of a pseudogene which increases resistance to sepsis (Wang et al 2006); the active allele (Casp12-L), while rare (<1%) in most Asian and European populations, is common in sub-Saharan Africa, up to 60% (Kachapati et al 2006); chimpanzees and other mammals have active Casp12. Besides association with infections, caspase12 is also associated with amyloid-induced neuronal apoptosis, which may be relevant to the apparent absence of Alzheimer's disease in chimpanzees and other great apes (Finch 2010; Chimpanzee Sequencing and Analysis Consortium 2005). Another relevant allele system is apoE, which influences cytokine secretions (Vitek et al 2009), as well as lifespan, Alzheimer's and heart disease. The main histocompatibility gene complex (Mhc) also has allelic variations relevant to somatic cell resilience.

Concluding remarks

The link between in vitro cell resilience and species lifespan is a fascinating and important paradigm in the biology of aging. We have argued that the evolutionary selection for resistance to multiple types of inflammatory events underpins the general observation that cells in culture from long-lived species are stress resistant. This hypothesis further specifies aspects of Kirkwood's disposable soma theory that relate to inflammation (2005). We predict that longer-lived species are specifically more resistant to particular immune-related stressors and propose future studies based on this hypothesis.

Acknowledgements

The authors are grateful for financial support: CEF, Ellison Medical Foundation and NIA (AG-026572); VDL, AG20642, AG025135; JPM, BBSRC (BB/G024774/1); TEM, AG-026572.

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