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Age Related Cognitive Decline

Mechanisms Involved in Age-Related Cognitive Decline

Age-related cognitive decline is a complex process with multiple overlapping mechanisms that are not fully understood. Below is a discussion of current understandings regarding some of the processes that contribute to cognitive decline in older age.

Stem Cell Senescence

Groundbreaking studies in the 1990s revealed specialized regions of the human brain harbor stem cells, known as neural stem cells, that may continue to repair and regenerate brain tissue throughout life.8,32 Growth factors such as brain-derived neurotrophic factor (BDNF) and other signaling factors in the brain environment appear to stimulate neural stem cell proliferation and the formation of neurons and neuronal connections.33,34 The ability of the brain to form new neurons and connections and rearrange neural networks in response to signals from the environment is known as brain plasticity, or neuroplasticity.32

With age, neural stem cells become less responsive to stimulation and stem cell signaling can become dysregulated.35 This condition, known as stem cell senescence, is thought to be a major contributing factor in the diminishing plasticity that characterizes the aging brain.36-38

Circadian Rhythm Disturbance

The circadian rhythm is a natural cycle that affects the brain and the rest of the body in many important ways. Circadian clocks synchronize metabolic, physiologic, and behavioral rhythms with environmental cycles, such as light-dark cycles and daily eating patterns.39,40 Among the many bodily functions regulated by circadian signaling are acquisition of learning and consolidation and recall of memories.40,41 Desynchronization of the circadian clock, such as through shift work, chronic stress, and sleep disorders, can contribute to cognitive decline.40 Circadian rhythm disruption is thought to interfere with neurogenesis and reduce neuroplasticity.42

Cerebrovascular Dysfunction

The term “cerebrovascular” refers to the blood vessels supplying the brain. Cerebrovascular dysfunction, driven by aging and atherosclerosis of the blood vessels in the brain, results in decreased cerebral blood flow. With age, cerebral blood vessels become stiffer and less responsive to changing blood pressures and oxygen and nutrient demands. In addition, capillary beds in the brain become more susceptible to injury and inflammation, increasing risk of developing small blood clots and microbleeds that can destroy neurons and negatively impact cognitive function.43-46

The blood vessels that supply the brain have a unique structural feature called the blood‒brain barrier, made up of specialized junctions between endothelial cells—the cells that form the inner lining of blood vessels. In healthy individuals, these junctions exert tight control over the movement of compounds between the blood and the brain. The blood‒brain barrier has been observed to lose integrity with age, becoming increasingly permeable to potential toxins and pro-inflammatory factors.14


Aging is associated with elevated inflammatory signaling involving activated microglia, astrocytes, blood vessel endothelial cells, and other cell types, causing neuroinflammation. This leads to increased production of free radicals and other neurotoxins that damage neurons and trigger neuronal degeneration.11,47 Neuroinflammation also degrades the blood‒brain barrier, exposing neurons to more potential toxins.9 Conditions associated with systemic inflammation, such as lack of physical activity, poor diet, obesity, and type 2 diabetes have all been associated with age-related cognitive decline and dementia.21,48 An unhealthy gut microbiome is another possible source of inflammatory signaling that may contribute to deterioration of the blood‒brain barrier and neuroinflammation.49

Mitochondrial Dysfunction and Oxidative Stress

The brain uses about 20% of the resting body’s oxygen, and roughly 85% of that oxygen is consumed by brain cell mitochondria. The brain is particularly sensitive to mitochondrial dysfunction, and free radical production in the brain is exceptionally high.47,50 Free radical production in a healthy brain is balanced by powerful antioxidant defenses; however, in an aging brain, antioxidant enzymes like glutathione reductase and superoxide dismutase (SOD) are less active, leading to an imbalance that favors free radical production and creates an environment of high oxidative stress.47,50

Oxidative stress damages cellular and mitochondrial DNA, membranes, and proteins, contributing to decreased brain cell activity and increased mitochondrial dysfunction. Mitochondrial dysfunction results in lower ATP production and more free radical generation,50 and contributes to depletion of neural stem cells.51 Reduced energy for metabolic activity within brain cells leads to their diminished ability to engage in normal neuronal activities, including maintenance of cell membranes and production of myelin,13 as well as activities related to learning, memory, and cognition.47 In addition, oxidative stress increases inflammatory signaling, exacerbating neuronal damage and loss.48

Metabolic Disturbance

Metabolic disturbances like insulin resistance and obesity are implicated as contributors to cognitive impairment and dementia. It is thought that systemic inflammation caused by insulin resistance and obesity may drive neuroinflammation, brain insulin resistance, brain mitochondrial dysfunction, and brain oxidative stress. These conditions eventually lead to neuronal damage and cognitive decline.52,53

Disordered blood lipid levels and high blood glucose levels have consistently been found to correlate with cognitive dysfunction,52-54 and type 2 diabetes has been correlated with increased risk of mild cognitive impairment, as well as its progression to dementia.55 In addition, Alzheimer disease increases the risk of developing type 2 diabetes, suggesting a two-directional relationship.56 Although the mechanism underlying the connection is not fully established, the relationship between insulin resistance and Alzheimer dementia in particular is so compelling that it is sometimes referred to as “type 3 diabetes.”57

Concussion and Cognitive Decline

Concussion, also known as mild traumatic brain injury, is now widely recognized as a potential contributor to long-term cognitive dysfunction. Until recently, the effects of concussion were believed to resolve spontaneously in a matter of months in the majority of people. We now know that as many as half of all individuals with a single concussion experience chronic cognitive impairment.58 Repeated head traumas, which are common in athletes, may further increase long-term risks.59,60

Several mechanisms appear to be at play in the cognitive sequelae of concussion. Laboratory models of head injury suggest mild traumatic brain injury, particularly when repeated, may trigger a cascade of overlapping processes in the brain, such as60,61:

  • altered glucose metabolism and energy production by neuronal mitochondria
  • increased oxidative stress and oxidative damage to critical lipid brain structures
  • decreased cerebral blood flow
  • heightened activity of microglial cells, exacerbating neuroinflammation
  • disrupted blood‒brain barrier function
  • altered neurotransmission
  • decreased removal of amyloid and tau proteins

Furthermore, concussion may trigger neuronal death and initiate long-term degenerative processes.61 Studies using imaging techniques have revealed structural changes in brain tissue following head injury that are associated with decreases in attention, memory, and executive function.62 The effects of concussion appear to interact with age-related processes to accelerate loss of cognitive reserve and increase risk of cognitive impairment and dementia years later.63

Clinicians and researchers are still exploring strategies for minimizing the short- and long-term problems associated with concussion. In the meantime, protecting the head during high-risk activities is imperative. If you do experience a head injury, following recommendations for protecting the aging brain may be beneficial, whatever your age.

Abnormal Protein Accumulation

Beta [β]-amyloid and tau proteins occur normally in the brain, but when high levels of these proteins accumulate, they can trigger structural changes that disrupt neuronal function and signal transmission.2,64 In the aging brain, β-amyloid proteins accumulate in the spaces between neurons due to increased production, reduced clearance, or both.1,14 At high concentrations, β-amyloid proteins coalesce and form plaques around neurons.64 Tau proteins become damaged through a chemical process called phosphorylation. Aggregates of phosphorylated tau inside neurons trigger neurofibrillary tangle formation.64 Such plaques and tangles interfere with normal neuron-to-neuron communication, and are the hallmarks of Alzheimer disease, but recent studies reveal β-amyloid and phosphorylated tau may begin to accumulate decades before the onset of clinical dementia.65-68

High levels of β-amyloid and tau in the brain, as well as higher tau levels in the blood, have each been independently correlated with cognitive decline in the elderly and disease progression in those with mild cognitive impairment.65,69,70 While the nature of the relationship between abnormal protein accumulation and cognitive decline is not fully understood, phosphorylated tau proteins in particular appear to interfere with synapse function and induce a neuroinflammatory process leading to neuronal dysfunction even before tangles develop.65,71


“Epigenetics” is a term used to describe biological phenomena that affect how cells use the information stored in the genetic code. Epigenetic processes emphasize or de-emphasize the information contained in sections of the genome. Sections emphasized by epigenetic processes are said to be “expressed,” and de-emphasized sections are “silenced.” Epigenetic processes do not change the genetic code, but rather how cells “read” the code. Factors such as lifestyle habits, nutrition, and the environment (eg, exposure to air pollution) can influence epigenetic gene expression and silencing.

There is increasing evidence that epigenetics play a crucial role in learning, memory, and cognition in older adults and influence development of cognitive impairment and dementia.72 For example, epigenetic alterations affecting the brain’s circadian clock have been noted to impact function in key brain regions associated with cognitive decline.73 Factors that may trigger epigenetic changes associated with cognitive decline and dementia include disordered breathing patterns (such as hyperventilation syndrome), poor diet, alcohol overconsumption, and sleep deprivation.74

Disrupted Homocysteine Metabolism

Homocysteine is an amino acid derivative that has detrimental effects on blood vessels, contributing to vascular inflammation, thickening of the vessel walls, and endothelial dysfunction. It is a contributing factor in atherosclerosis and increases the risk of stroke.75 Homocysteine’s effects on brain function may be related to its impact on cerebral blood vessels,75 but some evidence also suggests homocysteine increases oxidative stress and neuroinflammation, and may have direct neurotoxic effects.76

A consensus statement by a panel of experts published in the Journal of Alzheimer’s Disease in 2018 stated that moderately elevated blood homocysteine levels (>11 micromoles per liter) are a contributing cause of age-related cognitive decline.27 High homocysteine levels have been linked to brain atrophy,77 and have consistently been associated with increased risk of cognitive impairment, dementia, and Alzheimer disease.27 Homocysteine is converted into cysteine via a pathway requiring pyridoxine (B6), or into methionine through a chemical process called methylation that is dependent on the B vitamins folate (B9) and cobalamin (B12). Folate and B12 deficiencies are common in the elderly and are the main cause of hyperhomocysteinemia.76 Treatment with these B vitamins has been shown to reduce homocysteine levels, slow brain atrophy, inhibit cognitive decline, and improve memory.27,77

Fibrinogen and Cognitive Decline

In a paper published in 2019, scientists at the Gladstone Institutes in San Francisco demonstrated that the blood-clotting protein fibrinogen, which can enter the brain after vascular damage weakens the blood‒brain barrier, may contribute to cognitive decline.78 Once fibrinogen enters the brain, the researchers found, it forms deposits that activate certain types of microglial cells (the immune cells of the central nervous system). Microglial activation generates reactive oxygen species and damages the dendritic spines, destroying the synaptic connections between neurons and causing cognitive decline. The scientists demonstrated that even very small quantities of fibrinogen in healthy brains caused a loss of synapses as seen in Alzheimer disease—and even in the absence of amyloid plaques. Blocking fibrinogen from binding microglia reduced synaptic deficits and cognitive decline in a mouse model of Alzheimer disease. The vascular component of Alzheimer pathology could be a reason why clinical trials aimed solely at reducing amyloid plaque have been unsuccessful. Combination therapies that address vascular changes as well as amyloid deposits may prove to be more successful in the future.

Several earlier studies established the connection between fibrinogen levels and cognitive decline. In a study of over 2,300 middle-aged to elderly subjects, higher plasma fibrinogen levels at baseline were predictive of cognitive decline after five years.79 Another study by the same research group linked a specific genotype associated with cognitive decline to higher fibrinogen levels.80 Higher fibrinogen levels after ischemic stroke have also been associated with poorer cognitive outcomes.81

Hormone Imbalance

The brain is an integral part of the body’s hormonal network, regulating hormone production and responding to hormone signals. The hypothalamic-pituitary-adrenal (HPA) axis and the hypothalamic-pituitary-gonadal (HPG) axis demonstrate the integrated relationship between the brain and hormone-producing glands. Hormones such as cortisol, dehydroepiandrosterone (DHEA), estrogen, and testosterone affect brain structure and function. Age-related diminishment in levels of these hormones and dampening of the brain’s responsiveness to hormone signaling may impact susceptibility to cognitive decline and dementia.82

Estrogen. Estrogen modulates brain function by enhancing cerebral blood flow, activating nerve growth factors, and preventing neuronal damage. It also appears to have a critical impact on mitochondrial energy production. In women, the drop in estrogen levels that occurs during perimenopause may be a contributing factor in age-related cognitive decline.83,84 Indeed, many women report changes in cognitive function around the time of menopause, although objective measures suggest this may be more profound with surgical menopause than natural menopause. Clinical trials in women suggest initiating estrogen therapy soon after menopause may have the greatest benefit in lowering dementia risk later in life. In fact, initiating estrogen therapy at an older age has been associated with no effects or detrimental effects on cognitive function.84,85 One complicating factor in clinical trials is the use of progesterone in combination with estrogen: while natural progesterone may augment the neuroprotective effects of estrogen, synthetic progestins such as medroxyprogesterone acetate (MPA) (which are typically used with estrogen in postmenopausal hormone therapy) appear to have the opposite effect.84 More information is available in Life Extension’s Female Hormone Restoration protocol.

Testosterone. Testosterone is an important regulator of cognition and mood, and lower levels in middle-aged and elderly men have been associated with depressive symptoms, worse cognitive performance, and increased risk of dementia in some studies.86 In men 70 years and older, greater reductions in testosterone levels have been correlated with increased cognitive decline.87 Some research suggests testosterone therapy may improve mental health, quality of life, and aspects of cognitive function in men with low levels.82,86 In women, however, higher testosterone levels in older age appear to be associated with more rapid cognitive decline,88 but this finding is complicated by other data suggesting testosterone replacement therapy may benefit cognitive function in the short-term in women whose ovaries have been surgically removed.89 More research is needed to clarify the potential role of testosterone replacement on cognitive function in women.

Cortisol. Cortisol, a glucocorticoid hormone produced by the adrenal glands in response to HPA axis activation, is a critical moderator of the stress response. Cortisol also affects mood, attention, and memory, as well as immune, metabolic, and other physiologic functions.82 The HPA axis and resulting cortisol release are normally regulated by circadian signals; under healthy conditions, cortisol levels show a clear diurnal cycle, peaking in the morning and dipping at night.90

In older adults, average cortisol levels are higher and the circadian rhythm of cortisol release is blunted. This may be partly related to diminished negative-feedback control over adrenal stimulation.82,90 Chronic or repetitive stress can add to persistent dysregulation of HPA axis signaling and cortisol release, and is linked to depression and anxiety, brain atrophy, cognitive impairment, and dementia.82,90 Exercise and mindfulness training may help reduce stress, repair cortisol regulation, and slow cognitive decline.90,91

Dehydroepiandrosterone (DHEA). DHEA is a precursor to other steroidal hormones such as estrogen, progesterone, and testosterone. In addition, DHEA has a range of direct hormonal actions. Most DHEA in blood is in the form of DHEA-sulfate (DHEA-s). DHEA is produced mainly in the adrenal glands, but smaller amounts are produced in the ovaries and testes. Levels of both DHEA and DHEA-s drop with age, such that levels in elderly individuals may be
80–90% lower than in younger individuals.92,93 A large research review concluded higher blood levels of DHEA-s are associated with better cognitive performance in men and women.94 Brain DHEA and DHEA-s concentrations are substantially higher than blood concentrations, and it has recently been proposed that DHEA may also be synthesized in the brain.93,95 Preclinical evidence suggests DHEA may contribute to cortisol regulation, reduce neuroinflammation and brain oxidative stress, and promote neuronal growth.93,95,96

Postoperative Cognitive Dysfunction

Postoperative cognitive dysfunction refers to a persistent cognitive impairment following surgery, frequently affecting orientation, attention, perception, consciousness, and judgement.97 Many surgery patients experience acute cognitive symptoms shortly after surgery, known as postoperative delirium, which lasts up to about four days. Cognitive changes such as confusion, reduced attention, and decreased awareness of surroundings are hallmarks of postoperative delirium. In about 10% of surgical patients, a more persistent cognitive impairment occurs. Older patients and those with pre-existing cognitive impairment are at higher risk of chronic postoperative cognitive effects.98 Cerebrovascular problems have also been linked to increased risk of postoperative cognitive dysfunction.99 Postoperative cognitive decline lengthens recovery time and hospital stays and is associated with poorer surgical outcomes.97

Although its cause is not entirely known, evidence suggests surgical trauma initiates an inflammatory response that, through communication between systemic and brain immune cells, triggers neuroinflammation. Both systemic and brain inflammation can also induce blood‒brain barrier dysfunction, giving rise to more inflammatory activity in brain tissue.100,101 Older age increases the risk of postoperative cognitive dysfunction, possibly due to the immune dysregulation that characterizes the aging immune system.102 Inflammation also increases oxidative stress and depletes the body’s antioxidants, which may further contribute to neuronal damage and dysfunction.103 Anesthesia’s potential effects on cognitive function add to the complexity, but observational studies have found that risk of postoperative cognitive dysfunction may not be related to the type of anesthesia used or even the type of surgery performed.101,103

Surgical recovery may be supported through a set of evidence-based pre-, peri-, and post-operative care protocols aimed at reducing stress, maintaining organ function, and accelerating restoration of gut function. They include measures such as counseling, physical activity, mental training, and nutritional interventions prior to surgery; ensuring adequate nutrition and avoiding unnecessarily long fasting periods immediately before procedures; using the least invasive surgical procedures and anesthesia techniques; judicious use of pain and other medications postoperatively; and resumption of healthy diet, promotion of daily rhythms and sleep, and early mobilization after surgery. These measures have been shown to enhance postsurgical recovery in general and may be useful in reducing the risk of postoperative cognitive decline.97,104