The ageing of populations worldwide is leading to an unprecedented increase in cancer cases and fatalities. Understanding the links between cancer and ageing is therefore more important than ever. How the interplay of ageing-associated changes affects cancer initiation and progression is complex, however, and some ageing processes probably foster cancer development whereas others hinder it, possibly in a tissue-specific manner. In the emerging age of cancer, how can our growing understanding of the biology of ageing inform cancer biology?
Subscribe to Journal
Get full journal access for 1 year
only $21.58 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Peto, J. Cancer epidemiology in the last century and the next decade. Nature 411, 390–395 (2001).
Edwards, B. K. et al. Annual report to the nation on the status of cancer, 1973–1999, featuring implications of age and aging on U.S. cancer burden. Cancer 94, 2766–2792 (2002).
Parkin, D. M., Bray, F. I. & Devesa, S. S. Cancer burden in the year 2000. The global picture. Eur. J. Cancer 37 (Suppl. 8), S4–S66 (2001).
Frank, S. A. Dynamics of Cancer: Incidence, Inheritance, and Evolution (Princeton (NJ), 2007).
Jones, D. S., Podolsky, S. H. & Greene, J. A. The burden of disease and the changing task of medicine. N. Engl. J. Med. 366, 2333–2338 (2012).
Balducci, L. & Ershler, W. B. Cancer and ageing: a nexus at several levels. Nature Rev. Cancer 5, 655–662 (2005).
Peto, R. & Doll, R. There is no such thing as aging. BMJ 315, 1030–1032 (1997).
Christensen, K. et al. Cancer and longevity—is there a trade-off? A study of cooccurrence in Danish twin pairs born 1900–1918. J. Gerontol. A Biol. Sci. Med. Sci. 67, 489–494 (2012).
Anisimov, V. N. Carcinogenesis and aging 20 years after: escaping horizon. Mech. Ageing Dev. 130, 105–121 (2009).
de Magalhaes, J. P., Wuttke, D., Wood, S. H., Plank, M. & Vora, C. Genome-environment interactions that modulate aging: powerful targets for drug discovery. Pharmacol. Rev. 64, 88–101 (2012).
Baker, D. J. et al. Increased expression of BubR1 protects against aneuploidy and cancer and extends healthy lifespan. Nature Cell Biol. 15, 96–102 (2013).
Anisimov, V. N. The relationship between aging and carcinogenesis: a critical appraisal. Crit. Rev. Oncol. Hematol. 45, 277–304 (2003).
Stanta, G., Campagner, L., Cavallieri, F. & Giarelli, L. Cancer of the oldest old. What we have learned from autopsy studies. Clin. Geriatr. Med. 13, 55–68 (1997).
Vaupel, J. W. Biodemography of human ageing. Nature 464, 536–542 (2010).
de Magalhaes, J. P. in An Introduction to Gerontology (ed. Stuart-Hamilton, I.) 21–47 (Cambridge Univ. Press, 2011).
Kenyon, C. J. The genetics of ageing. Nature 464, 504–512 (2010).
Tacutu, R. et al. Human Ageing Genomic Resources: integrated databases and tools for the biology and genetics of ageing. Nucleic Acids Res. 41, D1027–D1033 (2013).
Matheu, A. et al. Delayed ageing through damage protection by the Arf/p53 pathway. Nature 448, 375–379 (2007).
Ikeno, Y. et al. Reduced incidence and delayed occurrence of fatal neoplastic diseases in growth hormone receptor/binding protein knockout mice. J. Gerontol. A Biol. Sci. Med. Sci. 64, 522–529 (2009).
Ikeno, Y., Bronson, R. T., Hubbard, G. B., Lee, S. & Bartke, A. Delayed occurrence of fatal neoplastic diseases in Ames dwarf mice: correlation to extended longevity. J. Gerontol. A Biol. Sci. Med. Sci. 58, 291–296 (2003).
Ng, S. T. et al. Growth hormone treatment induces mammary gland hyperplasia in aging primates. Nature Med. 3, 1141–1144 (1997).
de Magalhaes, J. P. & Faragher, R. G. Cell divisions and mammalian aging: integrative biology insights from genes that regulate longevity. Bioessays 30, 567–578 (2008).
Guevara-Aguirre, J. et al. Growth hormone receptor deficiency is associated with a major reduction in pro-aging signaling, cancer, and diabetes in humans. Sci. Transl Med. 3, 70ra13 (2011).
Coschigano, K. T. et al. Deletion, but not antagonism, of the mouse growth hormone receptor results in severely decreased body weights, insulin, and insulin-like growth factor I levels and increased life span. Endocrinology 144, 3799–3810 (2003).
Gunnell, D. et al. Height, leg length, and cancer risk: a systematic review. Epidemiol. Rev. 23, 313–342 (2001).
Freitas, A. A. & de Magalhaes, J. P. A review and appraisal of the DNA damage theory of ageing. Mutat. Res. 728, 12–22 (2011).
Goto, M., Miller, R. W., Ishikawa, Y. & Sugano, H. Excess of rare cancers in Werner syndrome (adult progeria). Cancer Epidemiol. Biomarkers Prev. 5, 239–246 (1996).
Hoeijmakers, J. H. DNA damage, aging, and cancer. N. Engl. J. Med. 361, 1475–1485 (2009).
Lombard, D. B. et al. DNA repair, genome stability, and aging. Cell 120, 497–512 (2005).
Freitas, A. A., Vasieva, O. & de Magalhaes, J. P. A data mining approach for classifying DNA repair genes into ageing-related or non-ageing-related. BMC Genomics 12, 27 (2011).
Hursting, S. D., Lavigne, J. A., Berrigan, D., Perkins, S. N. & Barrett, J. C. Calorie restriction, aging, and cancer prevention: mechanisms of action and applicability to humans. Annu. Rev. Med. 54, 131–152 (2003).
Harper, J. M., Leathers, C. W. & Austad, S. N. Does caloric restriction extend life in wild mice? Aging Cell 5, 441–449 (2006).
Weindruch, R. & Walford, R. L. Dietary restriction in mice beginning at 1 year of age: effect on life-span and spontaneous cancer incidence. Science 215, 1415–1418 (1982).
Pugh, T. D., Oberley, T. D. & Weindruch, R. Dietary intervention at middle age: caloric restriction but not dehydroepiandrosterone sulfate increases lifespan and lifetime cancer incidence in mice. Cancer Res. 59, 1642–1648 (1999).
Dhahbi, J. M., Kim, H. J., Mote, P. L., Beaver, R. J. & Spindler, S. R. Temporal linkage between the phenotypic and genomic responses to caloric restriction. Proc. Natl Acad. Sci. USA 101, 5524–5529 (2004).
Colman, R. J. et al. Caloric restriction delays disease onset and mortality in rhesus monkeys. Science 325, 201–204 (2009).
Mattison, J. A. et al. Impact of caloric restriction on health and survival in rhesus monkeys from the NIA study. Nature 489, 318–321 (2012).
Calle, E. E. & Kaaks, R. Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms. Nature Rev. Cancer 4, 579–591 (2004).
Longo, V. D. & Fontana, L. Calorie restriction and cancer prevention: metabolic and molecular mechanisms. Trends Pharmacol. Sci. 31, 89–98 (2010).
Flegal, K. M., Graubard, B. I., Williamson, D. F. & Gail, M. H. Cause-specific excess deaths associated with underweight, overweight, and obesity. JAMA 298, 2028–2037 (2007).
Liao, C. Y. et al. Fat maintenance is a predictor of the murine lifespan response to dietary restriction. Aging Cell 10, 629–639 (2011).
Breese, C. R., Ingram, R. L. & Sonntag, W. E. Influence of age and long-term dietary restriction on plasma insulin-like growth factor-1 (IGF-1), IGF-1 gene expression, and IGF-1 binding proteins. J. Gerontol. 46, B180–B187 (1991).
Grimberg, A. & Cohen, P. Role of insulin-like growth factors and their binding proteins in growth control and carcinogenesis. J. Cell. Physiol. 183, 1–9 (2000).
Dunn, S. E. et al. Dietary restriction reduces insulin-like growth factor I levels, which modulates apoptosis, cell proliferation, and tumor progression in p53-deficient mice. Cancer Res. 57, 4667–4672 (1997).
Herranz, D. & Serrano, M. SIRT1: recent lessons from mouse models. Nature Rev. Cancer 10, 819–823 (2010).
Herranz, D. et al. Sirt1 improves healthy ageing and protects from metabolic syndrome-associated cancer. Nature. Commun. 1, 3 (2010).
Fresno Vara, J. A. et al. PI3K/Akt signalling pathway and cancer. Cancer Treat. Rev. 30, 193–204 (2004).
Vijg, J. & Dolle, M. E. Large genome rearrangements as a primary cause of aging. Mech. Ageing Dev. 123, 907–915 (2002).
Jacobs, K. B. et al. Detectable clonal mosaicism and its relationship to aging and cancer. Nature Genet. 44, 651–658 (2012).
Laurie, C. C. et al. Detectable clonal mosaicism from birth to old age and its relationship to cancer. Nature Genet. 44, 642–650 (2012).
Stuart, G. R., Oda, Y., de Boer, J. G. & Glickman, B. W. Mutation frequency and specificity with age in liver, bladder and brain of lacI transgenic mice. Genetics 154, 1291–1300 (2000).
Dolle, M. E. et al. Rapid accumulation of genome rearrangements in liver but not in brain of old mice. Nature Genet. 17, 431–434 (1997).
Dolle, M. E., Snyder, W. K., Gossen, J. A., Lohman, P. H. & Vijg, J. Distinct spectra of somatic mutations accumulated with age in mouse heart and small intestine. Proc. Natl Acad. Sci. USA 97, 8403–8408 (2000).
Busuttil, R. A. et al. Intra-organ variation in age-related mutation accumulation in the mouse. PLoS ONE 2, e876 (2007).
Johnson, A. A. et al. The role of DNA methylation in aging, rejuvenation, and age-related disease. Rejuven. Res. 15, 483–494 (2012).
Peters, I. et al. Adiposity and age are statistically related to enhanced RASSF1A tumor suppressor gene promoter methylation in normal autopsy kidney tissue. Cancer Epidemiol. Biomarkers Prev. 16, 2526–2532 (2007).
Gorbunova, V., Seluanov, A., Mao, Z. & Hine, C. Changes in DNA repair during aging. Nucleic Acids Res. 35, 7466–7474 (2007).
Anisimov, V. N. Effect of age on dose-response relationship in carcinogenesis induced by single administration of N-nitrosomethylurea in female rats. J. Cancer Res. Clin. Oncol. 114, 628–635 (1988).
Collado, M., Blasco, M. A. & Serrano, M. Cellular senescence in cancer and aging. Cell 130, 223–233 (2007).
Campisi, J. Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors. Cell 120, 513–522 (2005).
de Magalhaes, J. P. From cells to ageing: a review of models and mechanisms of cellular senescence and their impact on human ageing. Exp. Cell Res. 300, 1–10 (2004).
Finkel, T., Serrano, M. & Blasco, M. A. The common biology of cancer and ageing. Nature 448, 767–774 (2007).
Gomes, N. M. et al. Comparative biology of mammalian telomeres: hypotheses on ancestral states and the roles of telomeres in longevity determination. Aging Cell 10, 761–768 (2011).
Minamino, T. et al. Endothelial cell senescence in human atherosclerosis: role of telomere in endothelial dysfunction. Circulation 105, 1541–1544 (2002).
Castro, P., Giri, D., Lamb, D. & Ittmann, M. Cellular senescence in the pathogenesis of benign prostatic hyperplasia. Prostate 55, 30–38 (2003).
Herbig, U., Ferreira, M., Condel, L., Carey, D. & Sedivy, J. M. Cellular senescence in aging primates. Science 311, 1257 (2006).
Panda, S., Isbatan, A. & Adami, G. R. Modification of the ATM/ATR directed DNA damage response state with aging and long after hepatocyte senescence induction in vivo. Mech. Ageing Dev. 129, 332–340 (2008).
Wang, C. et al. DNA damage response and cellular senescence in tissues of aging mice. Aging Cell 8, 311–323 (2009).
Molofsky, A. V. et al. Increasing p16INK4a expression decreases forebrain progenitors and neurogenesis during ageing. Nature 443, 448–452 (2006).
Krishnamurthy, J. et al. p16INK4a induces an age-dependent decline in islet regenerative potential. Nature 443, 453–457 (2006).
DePinho, R. A. The age of cancer. Nature 408, 248–254 (2000).
Rudolph, K. L. et al. Longevity, stress response, and cancer in aging telomerase-deficient mice. Cell 96, 701–712 (1999).
Chin, L. et al. p53 deficiency rescues the adverse effects of telomere loss and cooperates with telomere dysfunction to accelerate carcinogenesis. Cell 97, 527–538 (1999).
Krtolica, A., Parrinello, S., Lockett, S., Desprez, P. Y. & Campisi, J. Senescent fibroblasts promote epithelial cell growth and tumorigenesis: a link between cancer and aging. Proc. Natl Acad. Sci. USA 98, 12072–12077 (2001).
Coppe, J. P. et al. A human-like senescence-associated secretory phenotype is conserved in mouse cells dependent on physiological oxygen. PLoS ONE 5, e9188 (2010).
Liu, D. & Hornsby, P. J. Senescent human fibroblasts increase the early growth of xenograft tumors via matrix metalloproteinase secretion. Cancer Res. 67, 3117–3126 (2007).
Burd, C. E. et al. Monitoring tumorigenesis and senescence in vivo with a p16INK4a-luciferase model. Cell 152, 340–351 (2013).
Baker, D. J. et al. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature 479, 232–236 (2011).
Folkerd, E. J. & Dowsett, M. Influence of sex hormones on cancer progression. J. Clin. Oncol. 28, 4038–4044 (2010).
Ho, K. Y. et al. Effects of sex and age on the 24-hour profile of growth hormone secretion in man: importance of endogenous estradiol concentrations. J. Clin. Endocrinol. Metab. 64, 51–58 (1987).
Hammerman, M. R. Insulin-like growth factors and aging. Endocrinol. Metab. Clin. North Am. 16, 995–1011 (1987).
Miller, R. A. The aging immune system: primer and prospectus. Science 273, 70–74 (1996).
Franceschi, C. et al. Inflammaging and anti-inflammaging: a systemic perspective on aging and longevity emerged from studies in humans. Mech. Ageing Dev. 128, 92–105 (2007).
Fagiolo, U. et al. Increased cytokine production in mononuclear cells of healthy elderly people. Eur. J. Immunol. 23, 2375–2378 (1993).
Kaesberg, P. R. & Ershler, W. B. The importance of immunesenescence in the incidence and malignant properties of cancer in hosts of advanced age. J. Gerontol. 44, 63–66 (1989).
Ershler, W. B. & Longo, D. L. Aging and cancer: issues of basic and clinical science. J. Natl Cancer Inst. 89, 1489–1497 (1997).
Swann, J. B. & Smyth, M. J. Immune surveillance of tumors. J. Clin. Invest. 117, 1137–1146 (2007).
Mantovani, A., Allavena, P., Sica, A. & Balkwill, F. Cancer-related inflammation. Nature 454, 436–444 (2008).
Colotta, F., Allavena, P., Sica, A., Garlanda, C. & Mantovani, A. Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability. Carcinogenesis 30, 1073–1081 (2009).
Pedersen, M. et al. Circulating levels of TNFα and IL-6-relation to truncal fat mass and muscle mass in healthy elderly individuals and in patients with type-2 diabetes. Mech. Ageing Dev. 124, 495–502 (2003).
de Magalhaes, J. P., Curado, J. & Church, G. M. Meta-analysis of age-related gene expression profiles identifies common signatures of aging. Bioinformatics 25, 875–881 (2009).
Kim, S. et al. Circulating levels of inflammatory cytokines and risk of colorectal adenomas. Cancer Res. 68, 323–328 (2008).
Fontana, L., Eagon, J. C., Trujillo, M. E., Scherer, P. E. & Klein, S. Visceral fat adipokine secretion is associated with systemic inflammation in obese humans. Diabetes 56, 1010–1013 (2007).
Durnin, J. V. & Womersley, J. Body fat assessed from total body density and its estimation from skinfold thickness: measurements on 481 men and women aged from 16 to 72 years. Br. J. Nutr. 32, 77–97 (1974).
Pili, R. et al. Altered angiogenesis underlying age-dependent changes in tumor growth. J. Natl Cancer Inst. 86, 1303–1314 (1994).
Klement, H. et al. Atherosclerosis and vascular aging as modifiers of tumor progression, angiogenesis, and responsiveness to therapy. Am. J. Pathol. 171, 1342–1351 (2007).
Franco, S., Segura, I., Riese, H. H. & Blasco, M. A. Decreased B16F10 melanoma growth and impaired vascularization in telomerase-deficient mice with critically short telomeres. Cancer Res. 62, 552–559 (2002).
Hinkal, G., Parikh, N. & Donehower, L. A. Timed somatic deletion of p53 in mice reveals age-associated differences in tumor progression. PLoS ONE 4, e6654 (2009).
Peto, R., Roe, F. J., Lee, P. N., Levy, L. & Clack, J. Cancer and ageing in mice and men. Br. J. Cancer 32, 411–426 (1975).
Anisimov, V. N. Effect of host age on tumor growth rate in rodents. Front. Biosci. 11, 412–422 (2006).
Reed, M. J. et al. The effects of aging on tumor growth and angiogenesis are tumor-cell dependent. Int. J. Cancer 120, 753–760 (2007).
Ershler, W. B., Stewart, J. A., Hacker, M. P., Moore, A. L. & Tindle, B. H. B16 murine melanoma and aging: slower growth and longer survival in old mice. J. Natl Cancer Inst. 72, 161–164 (1984).
McCullough, K. D., Coleman, W. B., Smith, G. J. & Grisham, J. W. Age-dependent induction of hepatic tumor regression by the tissue microenvironment after transplantation of neoplastically transformed rat liver epithelial cells into the liver. Cancer Res. 57, 1807–1813 (1997).
Lancet, J. E., Willman, C. L. & Bennett, J. M. Acute myelogenous leukemia and aging. Clinical interactions. Hematol. Oncol. Clin. North Am. 14, 251–267 (2000).
Maas, H. A., Kruitwagen, R. F., Lemmens, V. E., Goey, S. H. & Janssen-Heijnen, M. L. The influence of age and co-morbidity on treatment and prognosis of ovarian cancer: a population-based study. Gynecol. Oncol. 97, 104–109 (2005).
Adami, H. O., Malker, B., Holmberg, L., Persson, I. & Stone, B. The relation between survival and age at diagnosis in breast cancer. N. Engl. J. Med. 315, 559–563 (1986).
Michels, K. B. & Ekbom, A. Caloric restriction and incidence of breast cancer. JAMA 291, 1226–1230 (2004).
Lee, C. et al. Reduced levels of IGF-I mediate differential protection of normal and cancer cells in response to fasting and improve chemotherapeutic index. Cancer Res. 70, 1564–1572 (2010).
Safdie, F. M. et al. Fasting and cancer treatment in humans: A case series report. Aging 1, 988–1007 (2009).
Firestein, R. et al. The SIRT1 deacetylase suppresses intestinal tumorigenesis and colon cancer growth. PLoS ONE 3, e2020 (2008).
Wang, R. H. et al. Interplay among BRCA1, SIRT1, and Survivin during BRCA1-associated tumorigenesis. Mol. Cell 32, 11–20 (2008).
Lara, E. et al. Salermide, a Sirtuin inhibitor with a strong cancer-specific proapoptotic effect. Oncogene 28, 781–791 (2009).
Li, L. et al. Activation of p53 by SIRT1 inhibition enhances elimination of CML leukemia stem cells in combination with imatinib. Cancer Cell 21, 266–281 (2012).
Brooks, C. L. & Gu, W. How does SIRT1 affect metabolism, senescence and cancer? Nature Rev. Cancer 9, 123–128 (2009).
Harrison, D. E. et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 460, 392–395 (2009).
Komarova, E. A. et al. Rapamycin extends lifespan and delays tumorigenesis in heterozygous p53+/− mice. Aging 4, 709–714 (2012).
Zakikhani, M., Dowling, R., Fantus, I. G., Sonenberg, N. & Pollak, M. Metformin is an AMP kinase-dependent growth inhibitor for breast cancer cells. Cancer Res. 66, 10269–10273 (2006).
Kalender, A. et al. Metformin, independent of AMPK, inhibits mTORC1 in a rag GTPase-dependent manner. Cell. Metab. 11, 390–401 (2010).
Libby, G. et al. New users of metformin are at low risk of incident cancer: a cohort study among people with type 2 diabetes. Diabetes Care 32, 1620–1625 (2009).
Strong, R. et al. Nordihydroguaiaretic acid and aspirin increase lifespan of genetically heterogeneous male mice. Aging Cell 7, 641–650 (2008).
Algra, A. M. & Rothwell, P. M. Effects of regular aspirin on long-term cancer incidence and metastasis: a systematic comparison of evidence from observational studies versus randomised trials. Lancet Oncol. 13, 518–527 (2012).
Rothwell, P. M. et al. Short-term effects of daily aspirin on cancer incidence, mortality, and non-vascular death: analysis of the time course of risks and benefits in 51 randomised controlled trials. Lancet 379, 1602–1612 (2012).
Dowling, R. J., Goodwin, P. J. & Stambolic, V. Understanding the benefit of metformin use in cancer treatment. BMC Med. 9, 33 (2011).
Buffenstein, R. Negligible senescence in the longest living rodent, the naked mole-rat: insights from a successfully aging species. J. Comp. Physiol. B 178, 439–445 (2008).
Caulin, A. F. & Maley, C. C. Peto's Paradox: evolution's prescription for cancer prevention. Trends Ecol. Evol. 26, 175–182 (2011).
Buffenstein, R. The naked mole-rat: a new long-living model for human aging research. J. Gerontol. A Biol. Sci. Med. Sci. 60, 1369–1377 (2005).
Seluanov, A. et al. Distinct tumor suppressor mechanisms evolve in rodent species that differ in size and lifespan. Aging Cell 7, 813–823 (2008).
Seluanov, A. et al. Hypersensitivity to contact inhibition provides a clue to cancer resistance of naked mole-rat. Proc. Natl Acad. Sci. USA 106, 19352–19357 (2009).
Liang, S., Mele, J., Wu, Y., Buffenstein, R. & Hornsby, P. J. Resistance to experimental tumorigenesis in cells of a long-lived mammal, the naked mole-rat (Heterocephalus glaber). Aging Cell 9, 626–635 (2010).
Gorbunova, V. et al. Cancer resistance in the blind mole rat is mediated by concerted necrotic cell death mechanism. Proc. Natl Acad. Sci. USA 109, 19392–19396 (2012).
George, J. C. et al. Age and growth estimates of bowhead whales (Balaena mysticetus) via aspartic acid racemization. Can. J. Zool. 77, 571–580 (1999).
Li, Y. & de Magalhaes, J. P. Accelerated protein evolution analysis reveals genes and pathways associated with the evolution of mammalian longevity. Age 35, 301–314 (2013).
United States Department of Health and Human Services, Centers for Disease Control and Prevention and National Cancer Institute. United States Cancer Statistics: 1999–2009 WONDER Online Database [online] (2013).
I thank everyone at the Lifestyle and Ageing Multidisciplinary Conference in Pisa, Italy, October 2010, for discussions that spurred this work and all participants at the European Science Foundation (ESF) Exploratory Workshop on Physics of Cancer in Varenna, Italy, September 2012, for fruitful discussions on these topics. Further thanks to J. Costa and to members of my laboratory, in particular S. Wood, D. Wuttke and R. Tacutu, for useful comments and suggestions. I am also grateful for support from the UK Biotechnology and Biological Sciences Research Council (BBSRC), the Wellcome Trust, the Royal Society, the Ellison Medical Foundation and from a Marie Curie International Reintegration Grant within EC-FP7 for supporting the work in my laboratory. I apologize to those whose work I could not cite owing to space limitations.
The author declares no competing financial interests.
About this article
International Immunopharmacology (2021)
Ageing Research Reviews (2021)
Neuroprotective Effects of Extracts from Tiger Milk Mushroom Lignosus rhinocerus Against Glutamate-Induced Toxicity in HT22 Hippocampal Neuronal Cells and Neurodegenerative Diseases in Caenorhabditis elegans
Porto Biomedical Journal (2021)
Extracts of the Tiger Milk Mushroom (Lignosus rhinocerus) Enhance Stress Resistance and Extend Lifespan in Caenorhabditis elegans via the DAF-16/FoxO Signaling Pathway