La edad es el principal factor de riesgo de la disfunción cognitiva. Sin duda es ley de vida, pero hoy en día se conocen bien los mecanismos por los que la edad contribuye a la neurodegeneración
Novel Strategies for Healthy Brain Aging
El ejercicio aeróbico es posiblemente una de las mejores estrategias para inhibir la mayor parte de signos ligados al envejecimiento del cerebro. Se debe principalmente a que activa vías moleculares que reducen inflamación y estrés oxidativo y mejorar neurogénesis y conectividad
Una de las mejores estrategias para el envejecimiento saludable del cerebro es el ejercicio aeróbico regular aeróbico. Los compuestos "antienvejecimiento" comúnmente estudiados pueden imitar algunos efectos del ejercicio en el cerebro, del ejercicio en el cerebro, pero es probable que los nuevos enfoques vías de detección de energía similares a las del ejercicio.
eficaces en este contexto.
Revisamos las pruebas que apoyan esta hipótesis centrándonos en las características biológicas del envejecimiento cerebral.
Key points
El envejecimiento cerebral es el mayor factor de riesgo de las enfermedades neurodegenerativas.
El ejercicio reduce los principales signos del envejecimiento cerebral.
Los compuestos antienvejecimiento pueden recapitular algunos de los efectos del ejercicio sobre las características del envejecimiento cerebral, pero no todos.
Los nuevos compuestos e intervenciones dirigidos a las vías de detección de energía similares al ejercicio pueden ser más eficaces en este contexto
INTRODUCTION
Los deterioros cognitivos relacionados con la edad están causados en parte por acontecimientos biológicos adversos en el cerebro conocidos como las "señas de identidad del envejecimiento cerebral" (Fig. 1). Este conjunto de procesos refleja en muchos aspectos los rasgos distintivos del envejecimiento (3) en los tejidos periféricos, pero también incluye varios fenómenos específicos del cerebro. Es importante destacar que los rasgos distintivos del envejecimiento cerebral también están implicados, y a menudo son más pronunciados, en la mayoría de las enfermedades neurodegenerativas. Por lo tanto, el envejecimiento cerebral y la neurodegeneración pueden formar parte de un continuo, y una combinación de rasgos distintivos/factores de riesgo puede determinar el desarrollo de la demencia o la enfermedad (2). Como resultado, hay un creciente interés en estrategias para inhibir las características del envejecimiento cerebral, lo que podría retrasar o prevenir la aparición de enfermedades neurodegenerativas.
El ejercicio es quizá la mejor estrategia para inhibir todas las principales características del envejecimiento cerebral, en gran medida porque activa vías celulares clave de detección de energía. Esta mejora del metabolismo/regulación de la energía con el ejercicio es importante porque las proteínas y vías celulares implicadas (en negrita) también pueden influir directamente en otras características. GSH, glutatión; VEGF, factor de crecimiento endotelial vascular.
El ejercicio aeróbico regular es una de las pocas formas basadas en pruebas de reducir el riesgo de deterioro cognitivo relacionado con la edad y de enfermedades neurodegenerativas (5). Por ello, se ha sugerido que el ejercicio debería ser una estrategia de primera línea para el envejecimiento saludable del cerebro. Aun así, existe un gran interés por las alternativas al ejercicio, incluidos los compuestos farmacológicos "antienvejecimiento" que pueden tener efectos similares o complementarios (especialmente en las sociedades occidentales, donde el sedentarismo es habitual y a muchos les resulta difícil mantener una rutina de ejercicio). Se han probado los efectos de muchos compuestos sobre la salud y la longevidad en organismos modelo, y varios en particular han demostrado suprimir los signos distintivos del envejecimiento en los tejidos periféricos y aumentar la esperanza de vida saludable en el Programa de Pruebas de Intervención (PTI) del Instituto Nacional sobre el Envejecimiento (6). Estos compuestos son algunos de los más estudiados en el amplio campo de la investigación sobre el envejecimiento y pueden ser prometedores para atenuar específicamente las características del envejecimiento cerebral.
The literature on how exercise affects the hallmarks of brain aging is relatively new, and the extent to which select/ITP anti-aging compounds influence the hallmarks of brain aging per se (and whether these agents can mimic the effects of exercise on the brain) also is an emerging topic. However, we and others have shown that exercise remains among the best approaches to reduce hallmarks of aging and increase health/function in peripheral tissues (4,7). Here, we hypothesize that 1) although most pharmacological agents known to increase lifespan in the ITP may reduce some hallmarks of brain aging, exercise will likely remain a more effective intervention for healthy brain aging because it stimulates key energy-sensing pathways that modulate multiple hallmarks, and 2) novel (non-ITP) compounds or interventions that target energy-sensing pathways similar to exercise will prove to be more effective for promoting healthy brain aging in this context. In the following sections, we review the hallmarks of brain aging and the effects of exercise on them, and we compare these to the effects of key ITP compounds on the same hallmarks as a framework for understanding the importance of energy-sensing pathways in healthy brain aging. Afterward, we discuss newer treatments and ideas for targeting bioenergetic signaling pathways similar to exercise that may hold the most promise as exercise alternatives.
Dysregulated Energy Metabolism: A Central Mechanism
Dysregulated energy metabolism is an underlying contributor to all hallmarks of brain aging. During aging, fasting glucose levels increase as cells become less effective at importing glucose in response to insulin (insulin resistance). Peripheral insulin resistance and elevated fasting glucose are linked with accelerated brain aging, poorer cognitive function, and dementia. Brain function is particularly sensitive to the adverse effects of insulin resistance as glucose is a key energy source for neurons, and this can be compounded by metabolic and cardiovascular changes with aging (e.g., dyslipidemia, increased triglycerides and low-density lipoprotein cholesterol). Consequently, sedentary lifestyles and unhealthy diets that impair peripheral function and metabolic health also are linked with accelerated brain aging (4,8).
Importantly, exercise is an energetic stress (reduced cellular energy levels) that peripheral tissues and the brain react to with many metabolic, mitochondrial, and cellular responses (known as hormesis). These adaptive responses involve the activation of energy-sensitive pathways that restore bioenergetic homeostasis in both peripheral tissues and in the brain. Key examples include upregulation of glucose transporters (GLUT) and increased signaling through the low-energy sensors AMP protein kinase (AMPK), sirtuin 1 (SIRT1; an NAD+ sensor), and the amino acid–sensing mammalian target of rapamycin (mTOR) pathway (Fig. 2) (8,9). The activation of these systems results in enhanced glucose utilization (GLUT), supports neuronal energy levels by regulating glycolysis and respiration (AMPK), controls the activity of transcription factors and energy-metabolizing enzymes (SIRT1), and modulates the turnover of proteins/macromolecules that can be used for energy (mTOR). These signaling proteins also may directly impact neural gene expression, synaptic plasticity, and memory formation. Moreover, prolonged exercise leads to glycogen depletion, fatty acid oxidation, and the production of ketone bodies, which are another important energy source for the brain and can independently activate these same sensors (8). In addition to all of this, exercise increases the expression of brain-derived neurotrophic factor (BDNF), which powerfully regulates neuron function and development as well as energy intake/behavior and can interact directly with or be activated by energy sensors like AMPK, mTOR, and SIRT1 (10,11). Importantly, all of these signaling pathways 1) contribute to stress resistance by enhancing cellular function and quality control, 2) have been reported to decline with aging, and 3) modulate other hallmarks of aging/brain aging, as emphasized in Figure 2 and described in the following sections (3,8,9). Thus, the activation of these energy-regulating pathways is central and perhaps the most important mechanism underlying the beneficial influence of exercise on the aging brain.
Accumulation of Oxidatively Damaged Molecules
Oxidatively damaged biomolecules accumulate with aging as a result of oxidative stress, an imbalance between antioxidant defenses and ROS production (3). These ROS can damage biomolecules like proteins, lipids, and DNA, as well as organelles — all of which can impair cellular function directly (because damaged components do not function properly) or indirectly (because damaged biomolecules may interfere with function in other cellular compartments). Neurons are especially sensitive to ROS because of their high, oxidizable lipid content and rate of oxidative metabolism (8).
Interestingly, exercise is associated with oxidative stress, as increased metabolism with exercise increases ROS generation. However, this effect is likely hormetic because exercise-associated oxidative stress leads to greater long-term antioxidant capacity (9). In fact, habitual aerobic exercise is associated with reduced levels of biomolecule damage in the brain. In old rodents, for example, both long-term running and swimming improve cognitive function and reduce ROS, oxidized proteins (carbonyls), and peroxidized lipids in the brain, in part by increasing antioxidants like glutathione and various neurotrophic factors (16) — many of which are modulated by AMPK, mTOR, and SIRT1. Long-term wheel running even reduces peroxidized lipids, improves memory, and protects against AD pathology in transgenic mouse models (17). Some evidence suggests that these beneficial effects require longer exercise interventions in older mice, which is consistent with the idea that exercise is a hormetic stress on the brain (18). Although there is little direct evidence for the effects of exercise on oxidative damage in the human brain, clinical studies have shown that exercise increases antioxidant defenses and reduces pro-oxidant processes systemically (9), and, similar effects likely occur in the brain.
Reduced Molecular Repair and Disposal
One main reason for both mitochondrial dysfunction and oxidative damage accumulation with aging is reduced activity of cellular repair and disposal systems. Many reports have documented systemic, age-related reductions in 1) autophagic-lysosomal degradation of proteins and organelles, and 2) activity of the proteasome (degrading old/damaged proteins). These systems are critical in neurons, which are postmitotic and must maintain their functional capacity throughout the lifespan. Moreover, the accumulation of undegraded, damaged, or aggregated proteins due to reduced autophagy and proteasome activity is central to the pathology of many neurodegenerative diseases (e.g., amyloid beta plaques in AD, alpha synuclein deposits in PD) (2).
Exercise increases autophagy and proteasome activity in both preclinical models and clinical settings (9), and although there is limited direct evidence for these effects in the brain, rodent studies indicate that swimming enhances autophagy and mitochondrial function in the hippocampus of older animals (19) and may protect against pharmacologically induced “premature” brain aging by activating the same systems (20). Running also increases proteasome activity in the brain (21), which may explain reductions in smaller, damaged biomolecules (e.g., protein carbonyls). These effects of exercise on molecular quality control likely involve multiple signaling networks for which autophagy and the proteasome are common downstream effector mechanisms. For example, studies in mice show that exercise activates autophagy in the brain by increasing the activity of AMPK and SIRT1 (13). Exercise also increases mitophagy and enhances mitochondrial network dynamics, in part by activating PGC-1α (14). In transgenic mice, the activation of these protective quality control systems by exercise may even reduce neurodegenerative protein aggregation (22).
Dysregulated Calcium Homeostasis
Cellular control of important ions and minerals becomes dysregulated in most aged tissues, but impaired calcium (Ca2+) homeostasis with aging is a particular problem in neurons. Ca2+ plays a role in numerous brain functions, including neurotransmission, neuronal excitability, synaptic plasticity, and long-term memory consolidation. Ca2+ levels also modulate gene expression, as Ca2+ influx through N-methyl-d-aspartate (NMDA) receptors can activate transcription factors like cyclic AMP response element-binding protein (CREB) and PGC-1α. With aging, neuronal Ca2+ homeostasis becomes impaired due to increased Ca2+ influx and dysregulation of intracellular Ca2+ modulators like mitochondria. This leads to altered gene expression and neuronal function that are linked with cognitive decline and can also contribute directly to neuronal death via Ca2+-driven excitotoxicity (8).
There is limited direct evidence for the effects of exercise on calcium homeostasis in the context of brain aging per se. However, many studies show that exercise increases BDNF, which has been reported to reduce neurotoxic extrasynaptic Ca2+ influx mediated by the NMDA receptor (23). Some of the beneficial effects of exercise on neuronal mitochondria likely improve Ca2+ homeostasis as well, as exercise enhances mitochondrial Ca2+ handling. In fact, studies in transgenic mice show that exercise increases the expression of the protective mitochondrial sirtuin, SIRT3, and that this is required for protection against Ca2+-related excitotoxicity (24). Studies of neuronal Ca2+ homeostasis in humans are lacking, but there is strong interest in related systemic biomarkers like S100 calcium-binding protein β (S100β), which is linked with brain aging, injury, and neurodegeneration, and is reduced by exercise (25).
Impaired Adaptive Cellular Stress Response
All cells activate stress resistance networks (e.g., antioxidant and anti-inflammatory pathways) in response to stressors. In the brain, these adaptive responses are important in settings of electrochemical, ionic, and even psychological stress. With aging, however, most cells become markedly less effective at mounting adaptive stress responses (3). In neurons, this is partly due to age-related decreases in the expression/activity of stress sensors like AMPK and SIRT1, and protective neurotrophic factors, such as BDNF and nerve growth factor (NGF). These proteins stimulate gene expression that promotes antioxidant defenses, healthy mitochondrial function, and Ca2+ handling (8).
Aberrant Neuronal Network Activity
The brain relies on communication among billions of neurons. Optimal function of neuronal networks requires balanced activity of glutamatergic (excitatory) neurons and GABAergic (inhibitory) interneurons. However, during aging, activity within these circuits (largely white matter communication via myelinated axons) is dysregulated, which can result in hyperexcitability and excitotoxic damage. This may lead to degeneration of fiber systems involved in decision making and learning/memory (8,26).
Some studies have investigated the influence of exercise on neuronal network activity. One showed that pharmacologically induced brain aging is mitigated by swimming, which reduces neurotoxicity and improves synaptic transmission by influencing the expression of glutamate-receptor 1 and synaptophysin (a marker of synaptic integrity) in rats (29). Exercise may also confer neuroprotection by modulating GABA disinhibition (26) and by enhancing dendritic outgrowth, maintaining structural integrity, and improving long-term potentiation in aged animals via BDNF and other proteins also involved in energy sensing. These changes coincide with increased hippocampal glutamate synthesis and an increase in NGFs (30).
In humans, there is evidence that exercise may positively influence neuronal transmission and connectivity. For example, greater cardiovascular fitness in older adults is associated with improved prefrontal cortex (important for decision making) processing speed and heightened synaptic plasticity (31), and meta-analyses find that exercise is associated with greater hippocampus volume and may influence network functional connectivity in this region (32).
Inflammation
Neuroinflammation is characterized by increased numbers of immune-activated, proinflammatory astrocytes and microglia that secrete neurotoxic cytokines (26). This glial cell activation is linked with brain aging, MCI, and most neurodegenerative diseases. In fact, markers of neuroinflammation and related neurodegeneration [e.g., glial fibrillary acidic protein (GFAP) and neurofilament light chain (NFL)] even have been shown to increase with aging in cognitively unimpaired people (2). Evidence shows that exercise decreases brain inflammation, marked by lower levels of the proinflammatory transcription factor nuclear factor κΒ and tumor necrosis factor α (TNF-α), and that these changes are associated with improved spatial memory (26). Exercise even prevents obesity-induced cognitive decline in rodents by influencing inflammatory genes, reducing the number of reactive astroglia and microglia, and reducing major markers of hippocampal inflammation (33). Finally, in old mice, running reduces brain proinflammatory cytokine levels, in part by activating BDNF and RE1-silencing transcription factor (REST), which is linked with numerous neurological disorders (34).
In humans, peripheral inflammation has been linked with brain structural abnormalities, reduced cognitive function, and greater dementia risk. As an example, recent studies demonstrate that high levels of C-reactive protein (CRP; a common clinical marker of inflammation) are associated with reduced brain white matter integrity in older adults (35), and epidemiological data show that systemic inflammation may precede neurodegenerative diseases by decades. However, meta-analyses show that habitual exercise is associated with reduced proinflammatory cytokines including CRP and TNF-α (36).
Impaired DNA Repair
The accumulation of DNA damage is an important hallmark of aging, and it plays a causal role in several premature aging syndromes. DNA damage also is closely linked with brain aging, cognitive decline, and neurodegenerative diseases (8). The genomic damage that accumulates with aging can contribute to cellular senescence (in which cells cease dividing and begin to produce proinflammatory molecules) and apoptosis (programmed cell death), leading to functional decline of organs/systems (including the brain) and reduced longevity (3).
The mechanisms by which exercise reduces DNA damage during aging are not well understood, but evidence points toward several DNA repair pathways, many of which are modulated by SIRT1 and other energy sensors (37). Rodent studies have shown that running stimulates DNA repair in brain tissue by upregulating the expression of CREB and apurinic/apyrimidinic endonuclease 1, which is a key enzyme for DNA base excision repair (38). Treadmill exercise has also been shown to reduce hippocampal DNA fragmentation and neuronal apoptosis in rat models of traumatic brain injury (39). Moreover, in animal models of AD, treadmill exercise is associated with reduced DNA damage and fewer double-stranded breaks in the hippocampus (40).
CONCLUSIONS
Based on the available evidence, it seems likely that developing novel strategies to target central, exercise-relevant energy-sensing pathways is a particularly promising direction for future research aimed at promoting healthy brain aging. New strategies like those outlined above will need to be tested in preclinical models and then carefully controlled clinical studies for feasibility, safety, and efficacy — but given the importance of healthy brain aging and dementia prevention, we suspect that such endeavors will be well worth the effort.
Basándonos en las pruebas disponibles, parece probable que el desarrollo de estrategias novedosas dirigidas a las vías centrales de detección de energía relevantes para el ejercicio sea una dirección especialmente prometedora para la investigación futura dirigida a promover el envejecimiento saludable del cerebro. Nuevas estrategias como las descritas anteriormente tendrán que ser probadas en modelos preclínicos y luego en estudios clínicos cuidadosamente controlados para su viabilidad, seguridad y eficacia - pero dada la importancia del envejecimiento saludable del cerebro y la prevención de la demencia, sospechamos que tales esfuerzos merecerán la pena.
Novel Strategies for Healthy Brain Aging
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