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Deregulated Nutrient Sensing

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Lead Section

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Deregulated nutrient sensing is the loss of the cell's ability to detect and respond to nutrient levels, which affects metabolism by altering the balance between catabolism and anabolism leading to age-related obesity, diabetes, and other metabolic syndromes. Molecular pathways involved in nutrient sensing are conserved life span regulators and include caloric restriction, insulin and insulin-like growth factor signalling (IIS) and target of rapamycin (mTOR) signalling.[1]

Summary as of "The Hallmarks of Aging"

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“The Hallmarks of Aging” review, published in 2013, summarized the process of aging into nine hallmarks, one of which is deregulated nutrient sensing.[1] Deregulated nutrient sensing is when the body’s detection and response to fuel, such as glucose, becomes unregulated.[1] The review focuses on the insulin and insulin-like growth factor 1 (IGF-1) signaling (IIS) pathway, mTOR, AMPK (AMP-activated protein kinase), and sirtuins.[1]  Dietary restriction (DR) was also shown to extend longevity.[1]

The IIS pathway and its FOXO and mTOR targets have been well-maintained in evolution.[1]  Reduced signaling strength along this pathway has been shown to increase longevity in worms, flies, and mice, as well as mimic some of the effects of DR.[1]  However, there seemed to be a required balance where downregulation of the IIS pathway led to longevity, but extremely low levels of its components led to increased aging or even death.[2]  In worms and flies, transcription factor FOXO has shown to be relevant to aging, but little was known about the four FOXO members in mice.[1]  However, mice with increased levels of tumor suppressor PTEN have displayed downregulation of the IIS pathway, increased energy spending, and increased longevity.[1]

The mTOR kinase senses high nutrient levels and anabolism through the presence of amino acids.[1]  Downregulation of mTORC1, one of the two kinases of mTOR, mimics the effects of DR and increases longevity in yeast, worms, and flies, even with normal regulation of mTORC2.[3]  Knocking down a component of mTORC1, such as S6K1 was also sufficient to extend lifespan.[4] The addition of rapamycin also increased longevity in mice.[1]  Despite the beneficial effects of mTOR inhibition, side effects exist, such as cataracts, insulin resistance, and deficiencies in wound repair.[5] AMPK senses low nutrient levels and catabolism through the presence of AMP.[1]  Increased activity of this kinase increases lifespan and downregulates mTORC1, extending these benefits.[1]  Sirtuins also sense low energy levels through NAD+ levels.[1]  Likewise, increased sirtuin levels activate metabolic responses and are part of a positive feedback loop with AMPK.[6]

Progress since "The Hallmarks of Aging"

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Since the publication of the “Hallmarks of Aging” review, the components of deregulated nutrient sensing have been investigated further.  More information in regard to pathway components are currently being researched with the hope of better understanding the causes of deregulated nutrient sensing and its contribution to the aging phenotype. More treatments can be developed to protect against age-related disease when new information is discovered. A common trend is the interconnection of the hallmarks. The more research that is done, the more connections seem to be made. Below are some advances made since the "Hallmarks of Aging" review. Specifically, the mechanisms underlying caloric restriction and the AMPK pathway were further investigated. Additionally, sirtuins, briefly mentioned in the review, and sestrins, not mentioned at all, were found to play a large role in deregulated nutrient sensing.

Caloric Restriction
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The processes behind the effects of caloric restriction on longevity have been further investigated.[7] Caloric restriction is defined as consuming fewer calories, but not to the extent of malnutrition.[7] The lifespan benefits are conserved across species from yeast to primates.[7] It has been shown to reduce visceral fat, which produces increased metabolic flexibility.[7] Visceral fat promotes inflammation and dibetes, which explains why its reduction is beneficial.[7]

Caloric restriction also triggers autophagy, which supports healthy organelles, stem cell function, and immunology.[7] It does so by utilizing nutrient sensors, such as SIRT1, AMPK, and MTORC1 to activate autophagic responses, FOXO1, and preserve telomerase.[8][9] In particular, activating FOXO has been shown to play a role in the telomere attrition hallmark through improving telomerase activity, showing again how the hallmarks are connected.[7]

Calorie restriction mimetics are a new concept to alleviate the side effects of caloric restriction, such as anemia and loss of muscle mass.[7] For example, macronutrient intake has been shown mimic the effects of caloric restriction in mice fed ad libitum.[10] Specifically, carbohydrates and protein levels dictate dietary intake.[10] The longest lifespans were observed in mice with low-protein and high carbohydrate diets.[10] Even though these mice were fed ad libitum, they showed increased lifespan due to changes in diet.[10] Specifically, the low protein and high carbohydrate diet inhibits mTOR, which extends lifespan.[10] This highlights the importance of macronutrient intake on lifespan and healthspan.

AMPK and Adenosine Derivatives
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Maintenance of adenosine derivatives (AMP, ADP, and ATP) at constant levels is central to cell metabolism and energy homeostasis.[11] AMP and ADP are precursors to ATP, which tranports energy thoughout the cell for metabolism.[11] AMP biosynthesis was previously shown to be involved with increasing lifespan in yeast, but no work had been done with multi-cellular organisms.[11] Likewise, AMP:ATP ratios and increased AMPK activity were shown to be predictive of lifespan in C. elegans, but had yet to be researched in more complex organisms.[11] AMP biosynthesis, adenosine nucleotide ratios, and AMPK were more recently shown to be determinants of lifespan in Drosophila melanogaster.[11] The addition of adenine to the diet of flies reduced lifespan by interfering with the positive effects of dietary restriction.[11] Manipulating dietary adenine could alter metabolism to influence lifespan.[11]

Sirtuins
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Sirtuins are a family of proteins that are involved in a variety of signalling pathways.[12] In particular, one member of this family, sirtuin 1 (SIRT1), is an NAD+ deacetylase.[12] Activation of SIRT1 has been shown to improve metabolism and alleviate some age-associated phenotypes.[12] SRT1720 activates SIRT1.[12] Dietary supplementation of SRT1720 in mice fed on a standard diet improved both lifespan and healthspan.[12]

SIRT1 was also activated by temperature reduction in fish. In some organisms, temperature reduction was shown to increase lifespan.[13] However, little was known about the mechanism.[13] Researchers found that temperature reduction stimulates the synthesis of SIRT1 and FOXO3A/FOXO1A, which are both downstream regulators of the IIS pathway.[13] Additionally, they found that reactive oxygen species (ROS), which causes damage that leads to aging, was reduced with temperature reduction, furthering the connections between causes of aging.[13]

Sestrins
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Sestrins are a family of conserved proteins activated by stress. They are important in maintaining metabolic homeostasis by reducing ROS and regulating the AMPK and mTOR pathways. [14] Obese mice deficient in sestrins were shown to get diabetes sooner than mice without the deficiency.[14] Mice lacking sestrin 3 (Sesn3) in the liver displayed metabolic disorders, such as insulin resistance and glucose intolerance, typically seen with accelerated aging.[15] Conversely, Sensn3 transgenic mice were protected against these disorders, even with a high-fat diet.[15] These results were the effect of sestrin 3 activating mTORC2.[15]

  1. ^ a b c d e f g h i j k l m n López-Otín, Carlos; Blasco, Maria A.; Partridge, Linda; Serrano, Manuel; Kroemer, Guido. "The Hallmarks of Aging". Cell. 153 (6): 1194–1217. doi:10.1016/j.cell.2013.05.039. PMC 3836174. PMID 23746838.{{cite journal}}: CS1 maint: PMC format (link)
  2. ^ Renner, Oliver; Carnero, Amancio. "Mouse Models to Decipher the PI3K Signaling Network in Human Cancer". Current Molecular Medicine. 9 (5): 612–625. doi:10.2174/156652409788488766.
  3. ^ Laplante, Mathieu; Sabatini, David M. (2012-04-13). "mTOR signaling in growth control and disease". Cell. 149 (2): 274–293. doi:10.1016/j.cell.2012.03.017. ISSN 0092-8674. PMC 3331679. PMID 22500797.{{cite journal}}: CS1 maint: PMC format (link)
  4. ^ Selman, Colin; Tullet, Jennifer M.A.; Wieser, Daniela; Irvine, Elaine; Lingard, Steven J.; Choudhury, Agharul I.; Claret, Marc; Al-Qassab, Hind; Carmignac, Danielle (2009-10-02). "Ribosomal protein S6 kinase 1 signaling regulates mammalian lifespan". Science (New York, N.Y.). 326 (5949): 140–144. doi:10.1126/science.1177221. ISSN 0036-8075. PMC 4954603. PMID 19797661.{{cite journal}}: CS1 maint: PMC format (link)
  5. ^ Wilkinson, John E.; Burmeister, Lisa; Brooks, Susan V.; Chan, Chi-Chao; Friedline, Sabrina; Harrison, David E.; Hejtmancik, James F.; Nadon, Nancy; Strong, Randy (2017-04-30). "Rapamycin slows aging in mice". Aging cell. 11 (4): 675–682. doi:10.1111/j.1474-9726.2012.00832.x. ISSN 1474-9718. PMC 3434687. PMID 22587563.{{cite journal}}: CS1 maint: PMC format (link)
  6. ^ Price, Nathan L.; Gomes, Ana P.; Ling, Alvin J.Y.; Duarte, Filipe V.; Martin-Montalvo, Alejandro; North, Brian J.; Agarwal, Beamon; Ye, Lan; Ramadori, Giorgio (2012-05-02). "SIRT1 is required for AMPK activation and the beneficial effects of resveratrol on mitochondrial function". Cell metabolism. 15 (5): 675–690. doi:10.1016/j.cmet.2012.04.003. ISSN 1550-4131. PMC 3545644. PMID 22560220.{{cite journal}}: CS1 maint: PMC format (link)
  7. ^ a b c d e f g h López-Otín, Carlos; Galluzzi, Lorenzo; Freije, José M.P.; Madeo, Frank; Kroemer, Guido. "Metabolic Control of Longevity". Cell. 166 (4): 802–821. doi:10.1016/j.cell.2016.07.031.
  8. ^ Galluzzi, Lorenzo; Pietrocola, Federico; Levine, Beth; Kroemer, Guido. "Metabolic Control of Autophagy". Cell. 159 (6): 1263–1276. doi:10.1016/j.cell.2014.11.006. PMC 4500936. PMID 25480292.{{cite journal}}: CS1 maint: PMC format (link)
  9. ^ Makino, N.; Oyama, J.; Maeda, T.; Koyanagi, M.; Higuchi, Y.; Shimokawa, I.; Mori, N.; Furuyama, T. (2016-01-01). "FoxO1 signaling plays a pivotal role in the cardiac telomere biology responses to calorie restriction". Molecular and Cellular Biochemistry. 412 (1–2): 119–130. doi:10.1007/s11010-015-2615-8. ISSN 0300-8177. PMC 4718961. PMID 26708219.{{cite journal}}: CS1 maint: PMC format (link)
  10. ^ a b c d e Solon-Biet, Samantha M.; McMahon, Aisling C.; Ballard, J. William O.; Ruohonen, Kari; Wu, Lindsay E.; Cogger, Victoria C.; Warren, Alessandra; Huang, Xin; Pichaud, Nicolas. "The Ratio of Macronutrients, Not Caloric Intake, Dictates Cardiometabolic Health, Aging, and Longevity in Ad Libitum-Fed Mice". Cell Metabolism. 19 (3): 418–430. doi:10.1016/j.cmet.2014.02.009. PMC 5087279. PMID 24606899.{{cite journal}}: CS1 maint: PMC format (link)
  11. ^ a b c d e f g Stenesen, Drew; Suh, Jae Myoung; Seo, Jin; Yu, Kweon; Lee, Kyu-Sun; Kim, Jong-Seok; Min, Kyung-Jin; Graff, Jonathan M. "Adenosine Nucleotide Biosynthesis and AMPK Regulate Adult Life Span and Mediate the Longevity Benefit of Caloric Restriction in Flies". Cell Metabolism. 17 (1): 101–112. doi:10.1016/j.cmet.2012.12.006. PMC 3614013. PMID 23312286.{{cite journal}}: CS1 maint: PMC format (link)
  12. ^ a b c d e Mitchell, Sarah J.; Martin-Montalvo, Alejandro; Mercken, Evi M.; Palacios, Hector H.; Ward, Theresa M.; Abulwerdi, Gelareh; Minor, Robin K.; Vlasuk, George P.; Ellis, James L. (2014-03-13). "The SIRT1 activator SRT1720 extends lifespan and improves health of mice fed a standard diet". Cell reports. 6 (5): 836–843. doi:10.1016/j.celrep.2014.01.031. ISSN 2211-1247. PMC 4010117. PMID 24582957.{{cite journal}}: CS1 maint: PMC format (link)
  13. ^ a b c d Wang, Xia; Chang, Qingyun; Wang, Yu; Su, Feng; Zhang, Shicui (2014-12-01). "Late-Onset Temperature Reduction Can Retard the Aging Process in Aged Fish Via a Combined Action of an Anti-Oxidant System and the Insulin/Insulin-Like Growth Factor 1 Signaling Pathway". Rejuvenation Research. 17 (6): 507–517. doi:10.1089/rej.2014.1581. ISSN 1549-1684. PMC 4270139. PMID 25298234.{{cite journal}}: CS1 maint: PMC format (link)
  14. ^ a b Lee, Jun Hee; Budanov, Andrei V.; Karin, Michael. "Sestrins Orchestrate Cellular Metabolism to Attenuate Aging". Cell Metabolism. 18 (6): 792–801. doi:10.1016/j.cmet.2013.08.018. PMC 3858445. PMID 24055102.{{cite journal}}: CS1 maint: PMC format (link)
  15. ^ a b c Tao, Rongya; Xiong, Xiwen; Liangpunsakul, Suthat; Dong, X. Charlie (2015-04-01). "Sestrin 3 Protein Enhances Hepatic Insulin Sensitivity by Direct Activation of the mTORC2-Akt Signaling". Diabetes. 64 (4): 1211–1223. doi:10.2337/db14-0539. ISSN 0012-1797. PMC 4375082. PMID 25377878.{{cite journal}}: CS1 maint: PMC format (link)
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