Nutrient sensing and its role in aging

Highlights

‍

• Nutrient sensing is crucial for organism growth and survival. It is regulated by multiple biochemical pathways
• Four key signaling pathways for nutrient sensing are IGF-1, mTOR, AMPK, and sirtuins pathways 
• Deregulation of nutrient sensing has been linked with aging in animal models and humans
• Simultaneously, influencing these pathways through, for example, caloric restriction can lead to an increased life- and healthspan

‍

Introduction

Deregulated nutrient sensing is generally recognized as one of the nine key hallmarks of aging. Nutrient sensing mechanisms detect the changes in nutrient availability and allow the organism to maintain its homeostasis through various signaling pathways. These pathways also impact both production and degradation of proteins, thus regulating the proteins' abundance. Multiple studies have also shown that, by influencing these pathways, one can modulate aging in multiple organisms. The regulation of nutrient sensing explains the positive impact of such approaches to longevity as calorie restriction. In this article, we will focus on the four key nutrient-sensing mechanisms and discuss the implications of their deregulation.

‍

‍

Insulin signaling - the most conserved longevity pathway

Growth in many organisms is regulated by an interplay between the growth hormone (GH) and insulin-like growth factor (IGF-1). Moreover, IGF-1 invokes the same signaling pathway as insulin to inform the cells of the presence of glucose. This mechanism links IGF-1 and insulin signaling into a single pathway called the insulin and IGF-1 signaling (IIS) pathway. Across multiple species, the IIS pathway remains unchanged, making it the most evolutionarily conserved aging-controlled pathway in evolution (1).

Multiple studies have shown that the intensity of the IIS pathway signaling can significantly influence the lifespan of nematodes, fruit flies, and mice (2). Downregulation of this pathway is linked to longevity effects and is thought to contribute to the benefits of calorie restriction (CR). Also, downregulation of the IIS cascade can lead to improved mitochondrial metabolism and increased activity of the brown adipose tissue  (a special type of fat tissue crucial for thermoregulation, the amount of which decreases with age) (3,4). Upregulation of this pathway can result in the opposite, namely decreased mitochondrial metabolism and disrupted glucose and lipid homeostasis (5).

Counterintuitively, the levels of GH and IGF-1 tend to drop during normal and premature aging without any particular longevity effects (6). However, there is a unifying model proposed by Garinis et al. (7) that explains these seemingly contradictory observations. According to this model, if organisms have stably downregulated IIS pathway, they constantly possess low rates of metabolism and cell growth, resulting in less cellular “worn-out”. However, if a rapid decrease in IIS signaling happens during normal and premature aging, this serves as a defense mechanism. This defense mechanism attempts to protect the body against aging but ultimately becomes deleterious. Dysregulated extremely low insulin signaling can thus become dangerous, as was demonstrated in several studies (8,9).

‍

mTOR, the master of amino acids abundance

If the IIS pathway is mainly focused on glucose and lipids, the mTOR (mammalian target of rapamycin) pathway specializes in amino acid sensing. The protein itself, mTOR kinase, is a part of two larger protein complexes – mTORC1 and mTORC2 – that control all aspects of amino acid metabolism through complex interactions of mTOR with various signaling proteins (10). mTOR itself is the target of a molecule called rapamycin – a compound that first gained attention due to its anti-cancer properties.

If mTORC1 activity is downregulated genetically, it results in extended longevity in multiple model organisms (11). The studies also show that mTOR inhibition reproduces the phenotype observed in during calorie restriction in studies organisms. One of the main aging-attenuating interactions seems to be a downregulation of mTOR interaction with ribosomal proteins (12) and regulation of autophagy (13). 

During aging, dysregulation of the mTOR contributes to age-related obesity in mice (14). Moreover, deregulated mTOR nutrient sensing is increasingly gaining attention for its role in neurodegenerative diseases, such as Alzheimer’s disease (AD) (15,16). In mice, higher mTOR signaling is associated with amyloid accumulation, which is a distinct sign of AD (17). Postmortem studies in patients with AD and cognitive impairment (18) similarly demonstrated higher levels of activated mTOR in affected brain regions. 

Additionally to alleviating the above-described effects, mTOR downregulation can significantly expand health- and lifespan. A multicentric study from the National Institute on Aging showed a significant expansion of lifespan in mice due to the inhibition of mTOR with rapamycin (19). Nevertheless, despite the clear longevity benefits, extensive inhibition of mTOR can have undesirable side effects (as observed in mice), such as insulin resistance, impaired wound healing, and tissue degeneration (20).

‍

‍

AMPK, an AMP low-energy sensor

While IIS and mTOR signal nutrient availability, AMPK (AMP-activated protein kinase) plays the opposite role and detects nutrient scarcity. AMP (adenosine monophosphate) is a small endogenous molecule that plays a key role in cellular energy transport. The AMPK pathway regulates cell growth and survival, stress resistance, and autophagy (21). 

Upregulation of AMPK (i.e., nutrient scarcity) has been associated with healthy longevity. CR benefits have also been linked to AMPK activation, possibly leading to increased autophagic activity and reduced oxidative damage (1). The AMPK pathway is closely linked to the mTOR, with its activation resulting in a decreased activity of mTORC1. Several AMPK activators are investigated for their impact on human aging (21) and have shown anti-aging effects in animal models (22,23), among them metformin. Also, lifestyle modifications (24), including exercise and CR, have shown a positive impact on AMPK-related human aging characteristics. 

‍

Sirtuins, NAD+ low-energy sensors

‍Sirtuins are a family of proteins that, similarly to AMPK, sense nutrient scarcity. Unlike AMPK, their main sensor molecule is NAD+ (nicotinamide adenine nucleotide), another molecule involved in energy metabolism and production. Sirtuins have been extensively studied as potential anti-aging factors. Seven members of the family were shown to be able to alleviate various age-related conditions in mice (25). Not all of them, however, were able to induce longevity. For example, overexpression of SIRT1 improved genomic stability and metabolism efficiency but did not significantly increase lifespan (26). But for another member of the family, SIRT6, the evidence was more compelling. Mice with increased levels of SIRT6 not only had a longer lifespan compared to the control but also decreased IIS signaling (27). SIRT3 activation, through interaction with mitochondrial proteins, has also shown a longevity effect (similar to CR) (28). 

In addition, sirtuins are involved in a range of complex processes, including the creation of mitochondria, antioxidant defenses, and fatty acid metabolism (29). Research suggests that sirtuins and AMPK may participate in a positive feedback loop, creating a unified low-energy monitoring system (30). 

‍

‍

Other pathways in nutrient sensing

The four pathways described above are certainly the key mechanisms of nutrient sensing, but they should not be regarded as isolated and exclusive. Firstly, none of them are isolated – sirtuins influence AMPK, mTOR is linked to IGF-1, etc. Secondly, these are the most studied mechanisms but most certainly not the only ones. Many details of their interplay and new nutrient-sensing agents are being extensively studied. 

One example is the sestrins – a family of evolutionarily conserved proteins activated by stress. Their ability to regulate both AMPK and mTOR signaling allows uniting those into a single signaling pathway (31). The inactivation of sestrins in mammals leads to multiple disorders (resembling accelerated aging), including fat accumulation, mitochondrial dysfunction, diabetic progression, and muscle degeneration. It is known that these proteins can suppress oxidative stress, but sestrin function and regulation are still studied. Further investigation might provide further insights into age-associated diseases like sarcopenia and diabetes.

Another less-studied nutrient sensor is GCN2 (general control nonderepressive 2) (32) – a conserved protein that mediates the redox balance and assures healthy homeostasis in the cell. Contrary to mTOR, GCN2 is sensing an amino acid deficiency. GCN2 is also a part of the ISR (Integrated Stress Response) signaling pathway, which regulates not only cellular responses under amino acid deficiency but also under viral infection or other stress conditions. The impact of amino acid deficiency was mostly described through the lens of the mTOR pathway, but the role of GCN2 was largely disregarded. The studies in mice show that several age-related effects are unique to this pathway, and some longevity effects of dietary methionine restriction can be explained through the activation of GCN2 (33).

‍

Conclusions – decreased nutrient signaling enhances longevity

Nutrient sensing in living organisms is achieved through a variety of complex and specialized pathways. The main uniting thing about any of the known pathways is the idea that increased nutrient signaling accelerates aging, while decreased nutrient signaling extends lifespan. Many things are already known about what activates or inhibits the known pathways. There are promising pharmacological and lifestyle interventions that can improve the dysregulated nutrient states associated with aging. Undoubtedly, many more intricate details will be discovered to shed more light on the connection between these pathways and longevity.

‍

References

1. López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. The Hallmarks of Aging. Cell. 2013 Jun;153(6):1194–217.
2. Fontana L, Partridge L, Longo VD. Extending Healthy Life Span—From Yeast to Humans. Science. 2010 Apr 16;328(5976):321–6.
3. Garcia-Cao I, Song MS, Hobbs RM, Laurent G, Giorgi C, de Boer VCJ, et al. Systemic Elevation of PTEN Induces a Tumor-Suppressive Metabolic State. Cell. 2012 Mar;149(1):49–62.
4. Ortega-Molina A, Efeyan A, Lopez-Guadamillas E, Muñoz-Martin M, Gómez-López G, Cañamero M, et al. Pten Positively Regulates Brown Adipose Function, Energy Expenditure, and Longevity. Cell Metab. 2012 Mar;15(3):382–94.
5. Boucher J, Kleinridders A, Kahn CR. Insulin Receptor Signaling in Normal and Insulin-Resistant States. Cold Spring Harb Perspect Biol. 2014 Jan 1;6(1):a009191–a009191.
6. Schumacher B, van der Pluijm I, Moorhouse MJ, Kosteas T, Robinson AR, Suh Y, et al. Delayed and Accelerated Aging Share Common Longevity Assurance Mechanisms. Kim SK, editor. PLoS Genet. 2008 Aug 15;4(8):e1000161.
7. Garinis GA, van der Horst GTJ, Vijg J, H.J. Hoeijmakers J. DNA damage and ageing: new-age ideas for an age-old problem. Nat Cell Biol. 2008 Nov;10(11):1241–7.
8. Renner O, Carnero A. Mouse Models to Decipher the PI3K Signaling Network in Human Cancer. Curr Mol Med. 2009 Jun 1;9(5):612–25.
9. Mariño G, Ugalde AP, Fernández ÁF, Osorio FG, Fueyo A, Freije JMP, et al. Insulin-like growth factor 1 treatment extends longevity in a mouse model of human premature aging by restoring somatotroph axis function. Proc Natl Acad Sci. 2010 Sep 14;107(37):16268–73.
10. Laplante M, Sabatini DM. mTOR Signaling in Growth Control and Disease. Cell. 2012 Apr;149(2):274–93.
11. Johnson SC, Rabinovitch PS, Kaeberlein M. mTOR is a key modulator of ageing and age-related disease. Nature. 2013 Jan 17;493(7432):338–45.
12. Selman C, Tullet JMA, Wieser D, Irvine E, Lingard SJ, Choudhury AI, et al. Ribosomal Protein S6 Kinase 1 Signaling Regulates Mammalian Life Span. Science. 2009 Oct 2;326(5949):140–4.
13. Jahrling J, Laberge RM. Age-Related Neurodegeneration Prevention Through mTOR Inhibition: Potential Mechanisms and Remaining Questions. Curr Top Med Chem. 2015 Aug 7;15(21):2139–51.
14. Yang SB, Tien AC, Boddupalli G, Xu AW, Jan YN, Jan LY. Rapamycin Ameliorates Age-Dependent Obesity Associated with Increased mTOR Signaling in Hypothalamic POMC Neurons. Neuron. 2012 Aug;75(3):425–36.
15. Fluegge K. A model of lipid dysregulation and altered nutrient status in Alzheimer’s disease. Alzheimers Dement Transl Res Clin Interv. 2019 Jan;5(1):139–45.
16. Liu GY, Sabatini DM. mTOR at the nexus of nutrition, growth, ageing and disease. Nat Rev Mol Cell Biol. 2020 Apr 15;21(4):183–203.
17. Caccamo A, Majumder S, Richardson A, Strong R, Oddo S. Molecular Interplay between Mammalian Target of Rapamycin (mTOR), Amyloid-β, and Tau. J Biol Chem. 2010 Apr;285(17):13107–20.
18. Li X, Alafuzoff I, Soininen H, Winblad B, Pei JJ. Levels of mTOR and its downstream targets 4E-BP1, eEF2, and eEF2 kinase in relationships with tau in Alzheimer’s disease brain: Abnormal translation control in Alzheimer’s disease. FEBS J. 2005 Aug 3;272(16):4211–20.
19. Harrison DE, Strong R, Sharp ZD, Nelson JF, Astle CM, Flurkey K, et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature. 2009 Jul;460(7253):392–5.
20. Wilkinson JE, Burmeister L, Brooks SV, Chan CC, Friedline S, Harrison DE, et al. Rapamycin slows aging in mice: Rapamycin slows aging in mice. Aging Cell. 2012 Aug;11(4):675–82.
21. Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA, Stancu AL. AMPK activation can delay aging. Discoveries. 2015 Dec 31;3(4):e53.
22. Chen S, Zhou N, Zhang Z, Li W, Zhu W. Resveratrol induces cell apoptosis in adipocytes via AMPK activation. Biochem Biophys Res Commun. 2015 Feb;457(4):608–13.
23. Duca FA, Côté CD, Rasmussen BA, Zadeh-Tahmasebi M, Rutter GA, Filippi BM, et al. Metformin activates a duodenal Ampk–dependent pathway to lower hepatic glucose production in rats. Nat Med. 2015 May;21(5):506–11.
24. Fentz J, Kjøbsted R, Kristensen CM, Hingst JR, Birk JB, Gudiksen A, et al. AMPKα is essential for acute exercise-induced gene responses but not for exercise training-induced adaptations in mouse skeletal muscle. Am J Physiol-Endocrinol Metab. 2015 Dec 1;309(11):E900–14.
25. Guarente L. Sirtuins in Aging and Disease. Cold Spring Harb Symp Quant Biol. 2007 Jan;72(1):483–8.
26. Herranz D, Muñoz-Martin M, Cañamero M, Mulero F, Martinez-Pastor B, Fernandez-Capetillo O, et al. Sirt1 improves healthy ageing and protects from metabolic syndrome-associated cancer. Nat Commun. 2010 Dec;1(1):3.
27. Kanfi Y, Naiman S, Amir G, Peshti V, Zinman G, Nahum L, et al. The sirtuin SIRT6 regulates lifespan in male mice. Nature. 2012 Mar;483(7388):218–21.
28. Someya S, Yu W, Hallows WC, Xu J, Vann JM, Leeuwenburgh C, et al. Sirt3 Mediates Reduction of Oxidative Damage and Prevention of Age-Related Hearing Loss under Caloric Restriction. Cell. 2010 Nov;143(5):802–12.
29. Carafa V, Rotili D, Forgione M, Cuomo F, Serretiello E, Hailu GS, et al. Sirtuin functions and modulation: from chemistry to the clinic. Clin Epigenetics. 2016 Dec;8(1):61.
30. Ruderman NB, Julia Xu X, Nelson L, Cacicedo JM, Saha AK, Lan F, et al. AMPK and SIRT1: a long-standing partnership? Am J Physiol-Endocrinol Metab. 2010 Apr;298(4):E751–60.
31. Lee JH, Budanov AV, Karin M. Sestrins Orchestrate Cellular Metabolism to Attenuate Aging. Cell Metab. 2013 Dec;18(6):792–801.
32. Falcón P, Escandón M, Brito Á, Matus S. Nutrient Sensing and Redox Balance: GCN2 as a New Integrator in Aging. Oxid Med Cell Longev. 2019 May 22;2019:1–9.
33. Wanders D, Stone KP, Forney LA, Cortez CC, Dille KN, Simon J, et al. Role of GCN2-Independent Signaling Through a Noncanonical PERK/NRF2 Pathway in the Physiological Responses to Dietary Methionine Restriction. Diabetes. 2016 Jun 1;65(6):1499–510.

‍