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. 2010 Jan 14;32(2):231–237. doi: 10.1007/s11357-009-9128-x

Saturated fatty acid metabolism is key link between cell division, cancer, and senescence in cellular and whole organism aging

Judith H Ford 1,✉
PMCID: PMC2861752  PMID: 20431990

Abstract

Cellular senescence is an in vivo and in vitro phenomenon, accompanied by physiological changes including cessation of division and disturbances of organelle structure and function. Review of the literature was undertaken to determine whether there is evidence that whole organism aging and cell senescence share a common initiation pathway. In vivo aged cells of different lineages, including aged T lymphocytes, show high expression of the INK4A-p16 gene. In cell culture when telomeres are shortened past a key length or state, the Arf/Ink gene system (p16/p14 humans, p16/p19 mice) switches on and activates p53, which suppresses further cell division. The p53 gene is a key tumor suppressor and its deletion or mutation allows cancerous growth. The switching on of p53 also causes changes in fatty acid metabolism, especially down-regulation of both fatty acid synthase and stearoyl-CoA (delta-9) desaturase. The co-suppression of these genes together with enhanced uptake of extracellular fatty acids, leads to raised levels of cellular palmitate and induction of either apoptosis or senescence. In senescent cells, the fatty acid composition of the cellular membranes alters and leads to changes in both structure and function of organelles, especially mitochondria. Animal models of accelerated aging exhibit repression of stearoyl-CoA desaturase activity while anti-aging calorie restriction stimulates the same enzyme system. It is concluded that aging in cells and whole organisms share a common initiation pathway and that cellular senescence is protective against cancer. Healthy longevity is likely to be most enhanced by factors that actively suppress excessive cell division.

Keywords: Aging, p53, Ink4a, Arf, p16, fasn, Stearoyl-Coenzyme A-desaturase, Stearoyl-CoA-desaturase, Delta-9 desaturase, Telomere, Senescence, Calorie restriction, Palmitate, Palmitic acid, Cancer

Aging: a balance of senescence and cancer

Aging and the age-related decline in health is one of the most critical problems of modern civilization. Although considerable advances have been made in researching aging, progress in understanding this complex phenomenon is hampered by the volume of research in the different sub-disciplines and the difficulty of cross-discipline communication. This paper attempts to address one of these gaps by bringing together some of the literature from tumor cell biology and whole organism aging. The understanding that the p53 tumor suppressor gene plays a critical role in the prevention of human cancer (Oren 2003) is fundamental to the argument. It is concluded that changes in the p53 pathway induced at the cellular level at the time when cells reach a critical telomere state, and which switch off cell division, also induce permanent changes in fatty acid metabolism. Switching off or reducing the function of the stearoyl-CoA-desaturase 1 gene underlies changes in cellular membrane fatty acids that affect the structure and function of mitochondria and other organelles. Similar changes in fatty acids are seen in all rodent and human models of aging.

Telomeres, INK4A-Arf locus, and the p53 transcription factor

The observations that normal human fibroblasts have a limited lifespan in culture and that this seemed to be strongly influenced by the age of the donor, led to the Hayflick theory of cellular aging (Hayflick 1976). The maximum lifespan of the culture was known as the Hayflick limit after which senescent cells went into apoptosis (programmed cell death) or senescence. The relationship between donor age and cellular lifespan was later shown to be simplistic (Cristofalo et al. 1998) and it now appears that growth arrest is regulated by telomere state rather than by telomere length per se (Karlseder et al. 2002). However, although telomere regulation is a major inducer of senescence, activated oncogenes, DNA damage, oxidative stress, and inappropriate cell culture conditions can each rapidly induce senescence in cultured cells (Shay and Wright 2001).

In humans, both the p53 gene and the RB1 (retinoblastoma) gene monitor telomere function but in mice the p53 gene seems to be the only gene involved (Smogorzewska and de Lange 2002). The mechanism appears to be similar to other mechanisms that detect DNA damage and clearly involves the ATM (Ataxia telangectasia mutated gene)-p53 pathway (Takai et al. 2003). When telomeres shorten to a critical point, the p53 pathway is activated.

The INK4A-Arf locus has two gene products, p16Ink4a in both man and mouse and p14Arf in humans and p19Arf in mice. Both INK and Arf genes are potent tumor suppressors and both play a critical role in regulating the activities of the RBI and p53 genes. Ink4A/Arf was shown to be a robust biomarker of aging in mice (Krishnamurthy et al. 2004). Studies of senescence in vivo showed markedly increased expression of the genes in almost all rodent tissues with advancing age while there was little detectable change in other markers. Gene activation was restricted to well-defined areas in different organs but in each organ, cells of different lineage including epithelial and stromal cells were involved.

Further experiments with BubR1 insufficient mice suggest that the two INK4A-Arf genes may play different roles in senescence. When the two genes were separately inactivated, p16Ink4a exacerbated senescence while p19Arf attenuated senescence in skeletal muscle (Baker et al. 2008). The role of p16Ink4a is supported in human studies: expression of p16Ink4a increases sharply in aging human cells and high expression can be detected in peripheral blood T lymphocytes (Liu et al. 2009).

Arf genes activate p53 and cells move into either senescence (G1 arrest) or apoptosis (Lowe and Sherr 2003). Modulation by the Arf genes is complex and experiments using cells taken from mice with modified gene expression suggest that Arf acts rather like a circuit breaker that monitors the strength of mitotic signals. Under some circumstances cell division is allowed but where inappropriate oncogenic signals are received, p53 is induced. Loss of Arf or p53 function overwhelms normal tumor surveillance and genetic deficiencies result in increased susceptibility to cancer.

The p53 gene and tumor suppression

There is considerable evidence that the p53 gene is a component of the cellular response to DNA damage in mitosis as well as in response to telomere shortening. In either type of situation it causes cell cycle arrest at one of the cell cycle checkpoints (Harris 1996). Since chromosomes with very short telomeres have a strong tendency to both make divisional errors (aneuploidy) and to interchange DNA with other chromosomes causing structural chromosomal changes, the monitoring role reduces the cellular incidence of DNA and chromosomal error. The key role of p53, however, appears to be shutting down cell division completely. When a cell undergoes changes that could potentially lead to cancer, p53 is involved in activating appropriate repair mechanisms or in stimulating the chain of reactions that result in apoptosis or senescence, either of which effectively inhibits the cell from ever replicating again (Oren 2003). It is not surprising therefore that p53 mutation, deletion and/or suppression, is involved in a very wide range of tumors and that p53 antibodies, mostly to missense mutations, are found in human patients with a wide range of cancers (Soussi 2000).

Palmitic acid: key roles in cell metabolism, cell division, senescence, and apoptosis

p53, fasn, and senescence signaling

The p53 gene family consists of three genes in vertebrates but in invertebrates only a single gene is present. It is likely that this gene is the most important of the three p53 genes and its target gene fasn-1, fatty acid synthase, is conserved in all organisms from the nematode worm Caenorhabditis elegans to humans (D'Erchia et al. 2006). Not only is the gene conserved but the fasn-1 gene has been shown to have roles in both cellular proliferation and in apoptosis in germ cells. The key reaction product of the fasn-1 gene is palmitic acid (Smith 1994).

A recent study of fatty acid biosynthesis in senescent cells showed that a profound modification of fatty acid biosynthesis and fatty acid desaturation occurred in the senescence process in cultured human fibroblasts (Maeda et al. 2009). Cells were cultured to 80–90% confluence to induce senescence (G1 arrest) and tested for the expression of senescence associated B-galactosidase. Both fatty acid synthase and stearoyl-CoA-desaturase 1 (also known as delta 9 desaturase), the enzyme that converts saturated fatty acids palmitic and stearic to their monosaturated forms palmitoleic and oleic acids (Nakamura and Nara 2004), were markedly decreased in the senescent cells. However, exogenous fatty acids were preferentially incorporated into the triacylglycerol pool leading to relatively high levels of palmitic acid within the pool.

The cytoskeleton associated protein-4 (CKAP4) that links the endoplasmic reticulum to the cytoskeleton is reversibly palmitoylated and phosphorylated (Planey et al. 2009). Palmitoylation (the covalent attachment of palmitic acid to cysteine residues of membrane proteins) of CKAP4 plays a key role in opposing the expression of genes which are otherwise expressed during cell proliferation including tumorigenesis.

The cellular response to p53 inhibition of fasn is either senescence or apoptosis. The experiments of (Baker et al. 2008) suggest that this ‘decision’ is influenced by slightly different functionality of the two Arf genes. However, Chen et al. (2000) found that in H2O2-treated human diploid fibroblasts the cellular response depended on the stage of the cycle at the time of p53 activation. Apoptotic cells were mainly distributed in S phase while growth arrested cells were in G1 or G2/metaphase distributions. Apoptotic cells also exhibited much higher levels of p53 and reduction of p53 with human papilloma virus E6 protein inhibited the activation of caspase-3 and decreased the number of apoptotic cells. It seems that the determination of whether apoptosis or senescence occurs lies within the interaction between the Arf and p53 genes and the degree of activation of p53.

Role of palmitic acid in metabolic regulation, apoptosis, and senescence

It is commonly recognized that saturated fatty acids play a role in debilitating age-related illness such as type-2 diabetes and coronary heart disease but it is less well known that palmitic acid plays a key regulating role in the expression of a large number of genes. Palmitic acid was shown to affect the expression of 162 genes in liver cells (Swagell et al. 2005) but palmitic acid is also a regulator of genes that are not found in the liver nor apparently related to fat metabolism.

Elevated concentrations of palmitic acid are toxic to mitochondria and endoplasmic reticulum and can induce apoptosis without the involvement of reactive oxygen species. This has been demonstrated in many different cell types including cardiomycocytes (Hickson-Bick et al. 2002), hematopoietic cells (Paumen et al. 1997), pancreatic B-cells (Shimabukuro et al. 1998), and astrocytes (Blazquez et al. 2000). Relatively minor changes in palmitate concentration cause dramatic changes. For example incubation of BRIN-BD11 cells with increasing concentrations of palmitate (0.1–0.5 mM) resulted in a dose-dependent loss of cell viability. A 50% rate in cell death occurred between 0 and 0.15 mM and a further 30% cell death between 0.15 and 0.3 mM (Welters et al. 2006). Average palmitate levels in human serum are 0.125 ± 0.04 mM (Richieri and Kleinfeld 1995) indicating that toxic effects could occur within slightly elevated physiological ranges. It is also well established that fatty acid metabolites of cycloxygenase, lipoxygenase, and cytochrome P450 are essential components of programmed cell death (Tang et al. 2002). Thus signaling that increases cellular levels of palmitic acid can induce programmed cell death by more than one mechanism, including the induction of caspase (Ulloth et al. 2003).

Senescent cells are permanently growth arrested but are still functional at some level. In vitro induced senescent cells have the same changes in gene expression that are seen with age in human mesenchymal and hematopoietic cells (Wagner et al. 2009). Senescence particularly affects the structure and functions of organelles. Electron microscopic changes are observed in the mitochondria of senescence accelerated OXYS rats (Kolosova et al. 2001) and the fatty acid composition of both mitochondrial and microsomal membranes occur with aging in rats on an ad libitum diet and are modified by lifelong calorie restriction. The fatty acid changes with aging are consistent with reduction in the activity of the stearoyl-CoA-desaturase 1 gene and consequent increases in palmitic and stearic acids relative to palmitoleic and oleic acid.

Taken together, data on the fatty acid composition of organelles with aging and changes in the appearance of mitochondria with aging confirm that the reduced activity of stearoyl-CoA-desaturase 1 is an outcome of p53 activation that has an ongoing effect on mitochondrial function and cell function (Fig. 1).

Fig. 1.

Fig. 1

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Key stages of cellular aging include monitoring of cell division by the ARF/Ink gene complex. When telomeres reach a certain stage of shortening or function, Inkp16 signals and p53 is switched on. Activation of p53 inhibits the function of fatty acid synthase (fasn) and Stearoyl-CoA desaturase. This leads to raised cellular levels of palmitate which is taken up by cell membranes and organelles leading to either apoptosis or senescence

Fatty acid metabolism and aging

Changes in fatty acid metabolism, in particular increases in saturated fatty acids and their metabolic products, are characteristic of many age-related human diseases including cardiovascular disease and cancer (Volpe and Vagelos 1976). They also occur in the changes in gray matter that occur with advanced age (McNamara et al. 2008). These diseases are often regarded as lifestyle diseases and although there is little doubt that lifestyle plays a critical role in their etiology, the current findings on the changes in fatty acid metabolism that occur in response to p53 activation demonstrate that at least some of the changes in fatty acids are critical to survival.

A recent study has shown that changes in fatty acids consistent with the loss of stearoyl-CoA-desaturase 1 (delta-9) and delta-5 and 6 desaturase enzymic activity occur in adipose tissue in the mid-30 age group in fertile human females (Ford and Tavendale 2009). Similar dramatic changes in fatty acid synthesis have been shown to occur in mid-life in rats (Murthy et al. 1986) and these parallel the changes in stearoyl-CoA-desaturase 1 found in the membranes of aging organelles.

Key phenomena of aging and their (possible) relationship to altered fatty acid synthesis

Given that raised levels of saturated fatty acids, especially palmitic acid, occur as a result of p53 activation and that these fatty acids can cause both apoptosis and the mitochondrial changes seen in senescence, is this consistent with other models of mammalian aging?

Calorie restriction

Calorie restriction is the only factor that has reliably been shown to reduce aging but there is no consensus yet as to how this extends lifespan. In addition to the study on organelle membrane composition, several studies on calorie restriction have examined the effect on fatty acid metabolism. These data show highly significant decreases in the levels of long-chain fatty acids (Ayala et al. 2007). Energy restricted diets in rats specifically stimulate stearoyl-CoA-desaturase and effect massive decreases in levels of long-chain fatty acids (Hardy et al. 2002). Similarly, dietary protein and energy restriction in young pigs also induces stearoyl-CoA-desaturase (da Costa et al. 2004).

Senescence-accelerated mice

Senescence-accelerated mice (SAM) mice have been used as models of aging. The SAM mice seem to start life with normal development and maturation but due to rapid progression of senescence after maturity, the median survival time of the SAM mice is between 37% and 73% of the corresponding wild-type strains. The degree of senescence at 8 months of age is about 1.5 to 3.5 times normal. One of the SAM strains SAMP8 has been proposed as a possible model for Alzheimer disease (Morley 2002). SAMP8 mice have a marked decrease in stearoyl-CoA-desaturase and its mRNA by 10 months of age (Kumar et al. 1999) and it is thought that this may be involved in age-related impairments through its effects on membrane fluidity and cellular signaling pathways.

Human premature aging syndromes

Progeria is the most well known of a small number of premature aging syndromes in humans. Progeria was first described in 1886 and like other rare progeroid syndromes, involves a mutation in a gene whose function is related to DNA repair or metabolism. Some authors have interpreted the involvement of DNA repair dysfunction in these rare syndromes as evidence supporting the reactive oxygen species theory of aging, however the involvement of DNA repair genes is more likely to be involved in the activation of the p53 system as described above.

Fatty acids have not generally been the subject of research into the advanced-aging syndromes but long-term studies of serum lipids in a girl with progeria (Macnamara et al. 1970) showed extremely elevated levels of serum lipids. Total serum lipids were exceptionally high when the child was fed a diet including animal fat but regardless of diet, lipemia was excessive and there was delayed clearance of fats. This early paper did not define the specific fatty acids.

Mammalian aging, cell division, and fatty acids: implications for prevention of age-related illnesses

As has long been observed, aging is associated with both an increase in the incidence of most cancers and a range of chronic diseases and disability. It is also well known that many of the chronic diseases and disability are associated with fats and fatty acid metabolism. While physicians, physiologists, and epidemiologists have been undertaking considerable work in proving these associations, cell biologists and geneticists have been defining the genes and mechanisms that control the cell cycle and the transitions between the cell cycle and the onset of cancer. The work reviewed in this paper has shown that there is a signaling mechanism that switches on the p53 gene at the time of critical telomere shortening (or functional limitation) that causes crucial changes in fatty acid metabolism. Synthesis of fatty acids, in particular palmitic acid is shut down but levels of this fatty acid are maintained through the shutting down of the key enzyme stearoyl-CoA-desaturase whose role is to convert saturated fatty acids into monosaturated fatty acids. Other desaturase enzymes are also affected and these key changes go some way to explaining why fish oil supplementation is of such benefit in a range of age-related chronic illnesses (Yosefy et al. 1999).

Since reaching the point of telomere limitation is key to both the onset of cancer and senescence, it seems most likely that limiting unnecessary cell division is the key to longevity. Presumably, healthy aging will be enhanced by any behavior that reduces unnecessary cell division.

Calorie restriction is the one lifestyle option that is known to increase longevity and decrease age-related diseases. Calorie restriction significantly reduces cell division in vivo (Heller et al. 1990; Lok et al. 1990) but provides robust cellular proliferative responses when appropriate (Apte et al. 2002). There is no doubt that calorie restriction from a young age is greatly beneficial and enhances both longevity and healthy aging: the Japanese Okinawans provide an excellent example of such an outcome (Willcox et al. 2006). A recent study on caloric restriction in elderly humans demonstrates that memory performance can be enhanced by even later life caloric restriction (Witte et al. 2009). This study performed over 3 months in 50 normal to overweight subjects of mean age 60.5 years, showed a significant increase in verbal memory scores after caloric restriction, together with decreases in fasting insulin and high-sensitive C-reactive protein. Controls who ate their normal diet or a diet enhanced with unsaturated fatty acids showed no changes.

The papers reviewed in this paper show that there is evidence linking telomeres, cell division, cancer, and senescence through fatty acid metabolism. To date, changes in fatty acid metabolism have not been regarded as an intrinsic part of the cell division, telomere reduction-senescence pathway. The recognition that not only is fatty acid metabolism critical to this process but that this underlies the initial age-related damage observed in mitochondria, allows us to understand why some interventions, such as supplementation with fish oil, might improve some age-related problems but not others. The model presented that shows how these processes are linked through a series of checkpoints issues a strong warning against stimulation of cell division as a possible anti-aging therapy.

References

  1. Apte UM, Limaye PB, Ramaiah SK, Vaidya VS, Bucci TJ, Warbritton A, Mehendale HM. Upregulated promitogenic signaling via cytokines and growth factors: potential mechanism of robust liver tissue repair in calorie-restricted rats upon toxic challenge. Toxicol Sci. 2002;69:448–459. doi: 10.1093/toxsci/69.2.448. [DOI] [PubMed] [Google Scholar]
  2. Ayala V, Naudi A, Sanz A, Caro P, Portero-Otin M, Barja G, Pamplona R. Dietary protein restriction decreases oxidative protein damage, peroxidizability index, and mitochondrial complex I content in rat liver. J Gerontol A Biol Sci Med Sci. 2007;62:352–360. doi: 10.1093/gerona/62.4.352. [DOI] [PubMed] [Google Scholar]
  3. Baker DJ, Perez-Terzic C, Jin F, Pitel K, Niederlander NJ, Jeganathan K, Yamada S, Reyes S, Rowe L, Hiddinga HJ, Eberhardt NL, Terzic A, Deursen JM. Opposing roles for p16Ink4a and p19Arf in senescence and ageing caused by BubR1 insufficiency. Nat Cell Biol. 2008;10:825–836. doi: 10.1038/ncb1744. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Blazquez C, Galve-Roperh I, Guzman M. De novo-synthesized ceramide signals apoptosis in astrocytes via extracellular signal-regulated kinase. FASEB J. 2000;14:2315–2322. doi: 10.1096/fj.00-0122com. [DOI] [PubMed] [Google Scholar]
  5. Chen QM, Liu J, Merrett JB. Apoptosis or senescence-like growth arrest: influence of cell-cycle position, p53, p21 and bax in H2O2 response of normal human fibroblasts. Biochem J. 2000;347:543–551. doi: 10.1042/0264-6021:3470543. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Cristofalo VJ, Allen RG, Pignolo RJ, Martin BG, Beck JC. Relationship between donor age and the replicative lifespan of human cells in culture: a reevaluation. Proc Natl Acad Sci U S A. 1998;95:10614–10619. doi: 10.1073/pnas.95.18.10614. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. D'Erchia AM, Tullo A, Lefkimmiatis K, Saccone C, Sbisa E. The fatty acid synthase gene is a conserved p53 family target from worm to human. Cell Cycle. 2006;5:750–758. doi: 10.4161/cc.5.7.2622. [DOI] [PubMed] [Google Scholar]
  8. Costa N, McGillivray C, Bai Q, Wood JD, Evans G, Chang KC. Restriction of dietary energy and protein induces molecular changes in young porcine skeletal muscles. J Nutr. 2004;134:2191–2199. doi: 10.1093/jn/134.9.2191. [DOI] [PubMed] [Google Scholar]
  9. Ford JH, Tavendale R. Analysis of fatty acids in early mid-life in fertile women: implications for reproductive decline and other chronic health problems. Am J Hum Biol. 2009 doi: 10.1002/ajhb.20904. [DOI] [PubMed] [Google Scholar]
  10. Hardy RW, Meckling-Gill KA, Williford J, Desmond RA, Wei H. Energy restriction reduces long-chain saturated fatty acids associated with plasma lipids in aging male rats. J Nutr. 2002;132:3172–3177. doi: 10.1093/jn/131.10.3172. [DOI] [PubMed] [Google Scholar]
  11. Harris CC. Structure and function of the p53 tumor suppressor gene: clues for rational cancer therapeutic strategies. J Natl Cancer Inst. 1996;88:1442–1455. doi: 10.1093/jnci/88.20.1442. [DOI] [PubMed] [Google Scholar]
  12. Hayflick L. The cell biology of human aging. N Engl J Med. 1976;295:1302–1308. doi: 10.1056/NEJM197612022952308. [DOI] [PubMed] [Google Scholar]
  13. Heller TD, Holt PR, Richardson A. Food restriction retards age-related histological changes in rat small intestine. Gastroenterology. 1990;98:387–391. doi: 10.1016/0016-5085(90)90829-p. [DOI] [PubMed] [Google Scholar]
  14. Hickson-Bick DL, Sparagna GC, Buja LM, McMillin JB. Palmitate-induced apoptosis in neonatal cardiomyocytes is not dependent on the generation of ROS. Am J Physiol Heart Circ Physiol. 2002;282:H656–H664. doi: 10.1152/ajpheart.00726.2001. [DOI] [PubMed] [Google Scholar]
  15. Karlseder J, Smogorzewska A, Lange T. Senescence induced by altered telomere state, not telomere loss. Science. 2002;295:2446–2449. doi: 10.1126/science.1069523. [DOI] [PubMed] [Google Scholar]
  16. Kolosova NG, Aidagulova SV, Nepomnyashchikh GI, Shabalina IG, Shalbueva NI. Dynamics of structural and functional changes in hepatocyte mitochondria of senescence-accelerated OXYS rats. Bull Exp Biol Med. 2001;132:814–819. doi: 10.1023/A:1013014919721. [DOI] [PubMed] [Google Scholar]
  17. Krishnamurthy J, Torrice C, Ramsey MR, Kovalev GI, Al-Regaiey K, Su L, Sharpless NE. Ink4a/Arf expression is a biomarker of aging. J Clin Invest. 2004;114:1299–1307. doi: 10.1172/JCI22475. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Kumar VB, Vyas K, Buddhiraju M, Alshaher M, Flood JF, Morley JE. Changes in membrane fatty acids and delta-9 desaturase in senescence accelerated (SAMP8) mouse hippocampus with aging. Life Sci. 1999;65:1657–1662. doi: 10.1016/S0024-3205(99)00414-2. [DOI] [PubMed] [Google Scholar]
  19. Liu Y, Sanoff HK, Cho H, Burd CE, Torrice C, Ibrahim JG, Thomas NE, Sharpless NE. Expression of p16(INK4a) in peripheral blood T-cells is a biomarker of human aging. Aging Cell. 2009;8:439–448. doi: 10.1111/j.1474-9726.2009.00489.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Lok E, Scott FW, Mongeau R, Nera EA, Malcolm S, Clayson DB. Calorie restriction and cellular proliferation in various tissues of the female Swiss Webster mouse. Cancer Lett. 1990;51:67–73. doi: 10.1016/0304-3835(90)90232-M. [DOI] [PubMed] [Google Scholar]
  21. Lowe SW, Sherr CJ. Tumor suppression by Ink4a-Arf: progress and puzzles. Curr Opin Genet Dev. 2003;13:77–83. doi: 10.1016/S0959-437X(02)00013-8. [DOI] [PubMed] [Google Scholar]
  22. Macnamara BG, Farn KT, Mitra AK, Lloyd JK, Fosbrooke AS. Progeria. Case report with long-term studies of serum lipids. Arch Dis Child. 1970;45:553–560. doi: 10.1136/adc.45.242.553. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Maeda M, Scaglia N, Igal RA. Regulation of fatty acid synthesis and Delta9-desaturation in senescence of human fibroblasts. Life Sci. 2009;84:119–124. doi: 10.1016/j.lfs.2008.11.009. [DOI] [PubMed] [Google Scholar]
  24. McNamara RK, Liu Y, Jandacek R, Rider T, Tso P. The aging human orbitofrontal cortex: decreasing polyunsaturated fatty acid composition and associated increases in lipogenic gene expression and stearoyl-CoA desaturase activity. Prostaglandins Leukot Essent Fatty Acids. 2008;78:293–304. doi: 10.1016/j.plefa.2008.04.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Morley JE. The SAMP8 mouse: a model of Alzheimer disease? Biogerontology. 2002;3:57–60. doi: 10.1023/A:1015207429786. [DOI] [PubMed] [Google Scholar]
  26. Murthy VK, Oredipe OA, Stiles MR, Shipp JC. Increased fatty acid uptake, a factor in increased hepatic triacylglycerol synthesis in aging rats. Mech Ageing Dev. 1986;37:49–54. doi: 10.1016/0047-6374(86)90117-X. [DOI] [PubMed] [Google Scholar]
  27. Nakamura MT, Nara TY. Structure, function, and dietary regulation of delta6, delta5, and delta9 desaturases. Annu Rev Nutr. 2004;24:345–376. doi: 10.1146/annurev.nutr.24.121803.063211. [DOI] [PubMed] [Google Scholar]
  28. Oren M. Decision making by p53: life, death and cancer. Cell Death Differ. 2003;10:431–442. doi: 10.1038/sj.cdd.4401183. [DOI] [PubMed] [Google Scholar]
  29. Paumen MB, Ishida Y, Muramatsu M, Yamamoto M, Honjo T. Inhibition of carnitine palmitoyltransferase I augments sphingolipid synthesis and palmitate-induced apoptosis. J Biol Chem. 1997;272:3324–3329. doi: 10.1074/jbc.272.6.3324. [DOI] [PubMed] [Google Scholar]
  30. Planey SL, Keay SK, Zhang CO, Zacharias DA. Palmitoylation of cytoskeleton associated protein 4 by DHHC2 regulates antiproliferative factor-mediated signaling. Mol Biol Cell. 2009;20:1454–1463. doi: 10.1091/mbc.E08-08-0849. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Richieri GV, Kleinfeld AM. Unbound free fatty acid levels in human serum. J Lipid Res. 1995;36:229–240. [PubMed] [Google Scholar]
  32. Shay JW, Wright WE. Aging. When do telomeres matter? Science. 2001;291:839–840. doi: 10.1126/science.1058546. [DOI] [PubMed] [Google Scholar]
  33. Shimabukuro M, Zhou YT, Levi M, Unger RH. Fatty acid-induced beta cell apoptosis: a link between obesity and diabetes. Proc Natl Acad Sci U S A. 1998;95:2498–2502. doi: 10.1073/pnas.95.5.2498. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Smith S. The animal fatty acid synthase: one gene, one polypeptide, seven enzymes. FASEB J. 1994;8:1248–1259. [PubMed] [Google Scholar]
  35. Smogorzewska A, Lange T. Different telomere damage signaling pathways in human and mouse cells. EMBO J. 2002;21:4338–4348. doi: 10.1093/emboj/cdf433. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Soussi T. p53 Antibodies in the sera of patients with various types of cancer: a review. Cancer Res. 2000;60:1777–1788. [PubMed] [Google Scholar]
  37. Swagell CD, Henly DC, Morris CP. Expression analysis of a human hepatic cell line in response to palmitate. Biochem Biophys Res Commun. 2005;328:432–441. doi: 10.1016/j.bbrc.2004.12.188. [DOI] [PubMed] [Google Scholar]
  38. Takai H, Smogorzewska A, Lange T. DNA damage foci at dysfunctional telomeres. Curr Biol. 2003;13:1549–1556. doi: 10.1016/S0960-9822(03)00542-6. [DOI] [PubMed] [Google Scholar]
  39. Tang DG, La E, Kern J, Kehrer JP. Fatty acid oxidation and signaling in apoptosis. Biol Chem. 2002;383:425–442. doi: 10.1515/BC.2002.046. [DOI] [PubMed] [Google Scholar]
  40. Ulloth JE, Casiano CA, Leon M. Palmitic and stearic fatty acids induce caspase-dependent and -independent cell death in nerve growth factor differentiated PC12 cells. J Neurochem. 2003;84:655–668. doi: 10.1046/j.1471-4159.2003.01571.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Volpe JJ, Vagelos PR. Mechanisms and regulation of biosynthesis of saturated fatty acids. Physiol Rev. 1976;56:339–417. doi: 10.1152/physrev.1976.56.2.339. [DOI] [PubMed] [Google Scholar]
  42. Wagner W, Bork S, Horn P, Krunic D, Walenda T, Diehlmann A, Benes V, Blake J, Huber FX, Eckstein V, Boukamp P, Ho AD. Aging and replicative senescence have related effects on human stem and progenitor cells. PLoS ONE. 2009;4:e5846. doi: 10.1371/journal.pone.0005846. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Welters HJ, Diakogiannaki E, Mordue JM, Tadayyon M, Smith SA, Morgan NG. Differential protective effects of palmitoleic acid and cAMP on caspase activation and cell viability in pancreatic beta-cells exposed to palmitate. Apoptosis. 2006;11:1231–1238. doi: 10.1007/s10495-006-7450-7. [DOI] [PubMed] [Google Scholar]
  44. Willcox DC, Willcox BJ, Todoriki H, Curb JD, Suzuki M. Caloric restriction and human longevity: what can we learn from the Okinawans? Biogerontology. 2006;7:173–177. doi: 10.1007/s10522-006-9008-z. [DOI] [PubMed] [Google Scholar]
  45. Witte AV, Fobker M, Gellner R, Knecht S, Floel A. Caloric restriction improves memory in elderly humans. Proc Natl Acad Sci U S A. 2009;106:1255–1260. doi: 10.1073/pnas.0808587106. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Yosefy C, Viskoper JR, Laszt A, Priluk R, Guita E, Varon D, Illan Z, Berry EM, Savion N, Adan Y, Lugassy G, Schneider R, Raz A. The effect of fish oil on hypertension, plasma lipids and hemostasis in hypertensive, obese, dyslipidemic patients with and without diabetes mellitus. Prostaglandins Leukot Essent Fatty Acids. 1999;61:83–87. doi: 10.1054/plef.1999.0075. [DOI] [PubMed] [Google Scholar]

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