Aging brain - WikiHQ

Aging brain refers to biological and functional changes that occur in the brain as individuals advance in age. It encompasses both the normal alterations which are universally experienced and abnormalities induced by illnesses, diagnosed or not. The concept is most often used in relation to humans.

Since life extension is only pertinent if accompanied by healthspan extension, and, more importantly, by preserving brain health and cognition, finding rejuvenating approaches that act simultaneously in peripheral tissues and in brain function is a key strategy in the development of rejuvenation technology.

Aging is a major risk factor for most common neurodegenerative diseases, including mild cognitive impairment, dementias including Alzheimer's disease, cerebrovascular disease, Parkinson's disease, and Amyotrophic Lateral Sclerosis. While much research has focused on diseases of aging, there are few informative studies on the molecular biology of the aging brain in the absence of neurodegenerative disease or the neuropsychological profile of healthy older adults. However, research suggests that the aging process is associated with several structural, chemical, and functional changes in the brain as well as a host of neurocognitive changes. Recent reports in model organisms suggest that as organisms age, there are distinct changes in the expression of genes at the single neuron level. This page is an overview of the changes associated with human brain aging, including aging without concomitant diseases.

Structural changes

thumb|Human brain in the [[sagittal plane]]

thumb|[[Ventricular system|Ventricles of the brain]]

Aging entails many physical, biological, chemical, and psychological changes and the brain is no exception to this phenomenon. These various changes have attempted to be mapped by conceptual models like the Scaffolding Theory of Aging and Cognition (STAC) in 2009. The STAC model looks at factors like neural changes to the white matter, dopamine depletion, shrinkage, and cortical thinning. CT scans have found that the cerebral ventricles expand as a function of age. More recent MRI studies have reported age-related regional decreases in cerebral volume. Regional volume reduction is not uniform; some brain regions shrink at a rate of up to 1% per year, whereas others remain relatively stable until the end of the life-span. The brain is very complex, and is composed of many different areas and types of tissue, or matter. The different functions of different tissues in the brain may be more or less susceptible to age-induced changes. This ties into the common phrase, "if you don't use it, you lose it," which is another way of saying, "if you do not use it, your brain will devote less somatotopic space for it". One proposed mechanism for the observed age-related plasticity deficits in animals is the result of age-induced alterations in calcium regulation. The changes in the organism's abilities to handle calcium will ultimately influence neuronal firing and the ability to propagate action potentials, which in turn would affect the ability of the brain to alter its structure or function (i.e. its plastic nature). Due to the complexity of the brain, with all of its structures and functions, it is logical to assume that some areas would be more vulnerable to aging than others. Two circuits worth mentioning here are the hippocampal and neocortical circuits. It has been suggested that age-related cognitive decline is due in part not to neuronal death but to synaptic alterations. Evidence in support of this idea from animal work has also suggested that this cognitive deficit is due to functional and biochemical factors such as changes in enzymatic activity, chemical messengers, or gene expression in cortical circuits. Studies using Voxel-based morphometry have identified areas such as the insula and superior parietal gyri as being especially vulnerable to age-related losses in grey matter of older adults. but also with cognitive decline in the elderly.

Morphology and microstructure

Age-related decrease in gray matter volume was the largest contribution to changes in brain volume. Moreover, neuronal density appears to decrease, white matter microstructure gets altered and energy metabolism in the cerebellum gets altered. General cortical atrophy occurs in aging and e.g. the caudate nucleus volume appears to decrease.

There is converging evidence from cognitive neuroscientists around the world that age-induced cognitive deficits may not be due to neuronal loss or cell death, but rather may be the result of small region-specific changes to the morphology of neurons. One of the important differences between normal aging and pathological aging is the location of neurofibrillary tangles. Neurofibrillary tangles are composed of paired helical filaments (PHF). In normal, non-demented aging, the number of tangles in each affected cell body is relatively low As the non-demented individual ages, there is a general increase in the density of tangles, but no significant difference in where tangles are found. The exact impact of each of these mechanisms in affecting cognitive aging is unknown. Oxidative stress is the most controllable risk factor and is the best understood. The online Merriam-Webster Medical Dictionary defines oxidative stress as, "physiological stress on the body that is caused by the cumulative damage done by free radicals inadequately neutralized by antioxidants and that is held to be associated with aging." Hence oxidative stress is the damage done to the cells by free radicals that have been released from the oxidation process.

Compared to other tissues in the body, the brain is deemed unusually sensitive to oxidative damage. Increased oxidative damage has been associated with neurodegenerative diseases, mild cognitive impairment and individual differences in cognition in healthy elderly people. In 'normal aging', the brain is undergoing oxidative stress in a multitude of ways. The main contributors include protein oxidation, lipid peroxidation and oxidative modifications in nuclear and mitochondrial DNA. Each time a somatic cell replicates, the telomeric DNA component shortens. As telomere length is partly inheritable,). Increasing DNA damage with age has been reported in the brains of the mouse, rat, gerbil, rabbit, dog, and human. Young 4-day-old rats have about 3,000 single-strand breaks and 156 double-strand breaks per neuron, whereas in rats older than 2 years the level of damage increases to about 7,400 single-strand breaks and 600 double-strand breaks per neuron.

Lu et al. studied the transcriptional profiles of the human frontal cortex of individuals ranging from 26 to 106 years of age. This led to the identification of a set of genes whose expression was altered after age 40. They further found that the promoter sequences of these particular genes accumulated oxidative DNA damage, including 8-OHdG, with age (see DNA damage theory of aging). They concluded that DNA damage may reduce the expression of selectively vulnerable genes involved in learning, memory and neuronal survival, initiating a pattern of brain aging that starts early in life.

Immune system and fluids

Blood–brain barrier permeability, neuroinflammation and neurodegeneration, and gut microbiota-induced systemic chronic inflammation appear to be linked and interact with aging, e.g. as gut microbiota homeostasis could be disturbed by increasing age. According to a review, neuroinflammatory changes, "including microglial activation and production of inflammatory cytokines", occur with normal aging.

Fluids

Cerebral blood flow was shown to decrease 0.3-0.5% per year in healthy ageing. An efficiently functioning glymphatic system, involved in waste clearance, may be important for maintaining brain health and its transport efficiency appears to be declining with aging. Factors in the circulation have been shown to modulate ageing and to rejuvenate the brain.

Chemical changes

thumb|230px|Major dopamine pathways. As part of the [[Mesolimbic pathway|reward pathway, dopamine is manufactured in nerve cell bodies located within VTA and is released in the nucleus accumbens and the prefrontal cortex. The motor functions of dopamine are linked to a separate pathway, with cell bodies in the substantia nigra that manufacture and release dopamine into the striatum.|alt=A labelled line drawing of dopamine pathways superimposed on a drawing of the human brain.]]

thumb|230px|Dopamine and serotonin functions and pathways

In addition to the structural changes that the brain incurs with age, the aging process also entails a broad range of biochemical changes. More specifically, neurons communicate with each other via specialized chemical messengers called neurotransmitters. Several studies have identified a number of these neurotransmitters, as well as their receptors, that exhibit a marked alteration in different regions of the brain as part of the normal aging process.

Dopamine

An overwhelming number of studies have reported age-related changes in dopamine synthesis, binding sites, and number of receptors. Studies using positron emission tomography (PET) in living human subjects have shown a significant age-related decline in dopamine synthesis, notably in the striatum and extrastriatal regions (excluding the midbrain). Significant age-related decreases in dopamine receptors D1, D2, and D3 have also been highly reported. A general decrease in D1 and D2 receptors has been shown, Changes in dopamine levels may also cause age-related changes in cognitive flexibility. Postmortem studies on humans have indicated decreased binding capacities of serotonin and a decrease in the number of S1 receptors in the frontal cortex and hippocampus as well as a decrease in affinity in the putamen.

Glutamate

thumb|230px|Expression of [[glutamate transporter 1 in glial cell facilitates reuptake of glutamate and decreases extracellular glutamate concentration]]

Glutamate is another neurotransmitter that tends to decrease with age. Studies have shown older subjects to have lower glutamate concentration in the motor cortex compared to younger subjects. Often orientation is examined by distinguishing whether a person has a sense of time, place, and person. Deficits in orientation are one of the most common symptoms of brain disease, hence tests of orientation are included in almost all medical and neuropsychological evaluations. While research has primarily focused on levels of orientation among clinical populations, a small number of studies have examined whether there is a normal decline in orientation among healthy aging adults. Results have been somewhat inconclusive. Some studies suggest that orientation does not decline over the lifespan. For example, in one study 92% of normal elderly adults (65–84 years) presented with perfect or near perfect orientation. However some data suggest that mild changes in orientation may be a normal part of aging. For example, Sweet and colleagues concluded that "older persons with normal, healthy memory may have mild orientation difficulties. In contrast, younger people with normal memory have virtually no orientation problems" Attention is a broad construct that refers to "the cognitive ability that allows us to deal with the inherent processing limitations of the human brain by selecting information for further processing". Since the human brain has limited resources, people use their attention to zone in on specific stimuli and block out others.

If older adults have fewer attentional resources than younger adults, we would expect that when two tasks must be carried out at the same time, older adults' performance will decline more than that of younger adults. However, a large review of studies on cognition and aging suggest that this hypothesis has not been wholly supported. While some studies have found that older adults have a more difficult time encoding and retrieving information when their attention is divided, other studies have not found meaningful differences from younger adults. Similarly, one might expect older adults to do poorly on tasks of sustained attention, which measure the ability to attend to and respond to stimuli for an extended period of time. However, studies suggest that sustained attention shows no decline with age. Results suggest that sustained attention increases in early adulthood and then remains relatively stable, at least to the middle of the eighth decade of life. More research is needed on how normal aging impacts attention after age eighty.

It is worth noting that there are factors other than true attentional abilities that might relate to difficulty paying attention. For example, it is possible that sensory deficits impact older adults' attentional abilities. In other words, impaired hearing or vision may make it more difficult for older adults to do well on tasks of visual and verbal attention.

Brain activation patterns

The left inferior frontal junction and left anterior cuneus/precuneus were the only regions in a larger set of regions associated with executive functions, that consistently showed age differences in brain activity.

Changes in learning and behavioral flexibility

Learning is often more efficient in children and takes longer or is more difficult with age. A study using neuroimaging identified rapid neurotransmitter GABA boosting as a major potential explanation-component for why that is.

Behavioral flexibility can refer to efficiently and appropriately adapting to different situations and changing environmental demands, including the speed of adaptation, and to the capacity to develop solutions to novel problems or novel solutions to old problems. Studies indicate late-stage aging, and/or late-life dementias,

Genetic changes

Variation in the effects of aging among individuals can be attributed to both genetic, health, and environmental factors. As in so many other science disciplines, the nature versus nurture debate is an ongoing conflict in the field of cognitive neuroscience. By contrast, all brain regions and brain cells appear to have roughly the same epigenetic age in subjects who are younger than 80. These findings suggest that the cerebellum is better protected from aging effects, which in turn could explain why the cerebellum exhibits fewer neuropathological hallmarks of age related dementias compared to other brain regions.

Other

There is research and development of biomarkers of aging, detection systems and software systems to measure biological age of the brain. For example, a deep learning software using anatomic magnetic resonance images estimated brain age with relatively high accuracy, including detecting early signs of Alzheimer's disease and varying neuroanatomical patterns of neurological aging.

Delaying the effects of aging

The current state of biomedical technology does not allow to stop and reverse aging. However, one may potentially delay the effects and severity of its symptoms.

While there is no consensus of efficacy, the following are reported as delaying cognitive decline:

High level of education
Physical exercise
Maintaining a healthy diet, including omega-3 fatty acids, protective antioxidants as well as potentially anthocyanins- and flavanones-containing ones as in, more generally, Mediterranean diet patterns
Limiting stress, adequate sleep, managing sensory impairments, smoking cessation, limiting alcohol use, brain protection, treating cardiovascular risk factors
Caloric restriction and intermittent fasting
The microbiome also plays a role. Scientists have shown that transplantation of fecal microbiota from young donor mice into aged recipient mice substantially rejuvenates brain biomarkers of the latter, complementing similar results of a 2020 study. Diet and other factors influence the microbiome. Probiotics such as of L. plantarum may also have relevant effects.

Cognitive reserve

The ability of an individual to demonstrate attenuated cognitive signs of aging despite an aging brain is called cognitive reserve. However, the rate of decline in some cognitive subdomains, such as processing speed, may be less affected by premorbid IQ. The degree of association between IQ and cognitive reserve may vary between different types of dementia.

Research

"Super Agers"

Longitudinal research studies have recently conducted genetic analyses of centenarians and their offspring to identify protective factors against the negative effects of aging. In particular, the CETP gene is linked to prevention of cognitive decline and Alzheimer's disease. Specifically, valine CETP homozygotes but not heterozygotes experienced a relative 51% less decline in memory compared to a reference group after adjusting for demographic factors and APOE status.

In 1994, Religious Orders Study has begun. Its initial funding was also provided by NIA.

Inflammation

A study found that myeloid cells are drivers of a maladaptive inflammation element of brain-ageing in mice and that this can be reversed or prevented via inhibition of their EP2 signalling.

Cerebrospinal fluid

thumb|The cerebrospinal fluid circulates in the [[subarachnoid space around the brain and spinal cord, and in the ventricles of the brain]]

A study showed that infusing the nourishing cerebrospinal fluid from around brain cells of young mice into aged brains rejuvenates aspects of the brain, proving that it play a role in brain aging and inter alia identifying a protein FGF17 as a key target for potential therapeutics, including for anti-aging.

The subarachnoidal lymphatic-like membrane, whose discovery was reported around 2023, likely plays a role in cerebrospinal fluid functions and, as both a protective barrier and a host of immune cells that monitor the brain for infection and inflammation, appears to be substantially involved in major brain diseases and brain aging. It is "the host for a large population of myeloid cells [], the number of which increases in response to inflammation and aging".

Aging disparities

For certain demographics, the effects of normal cognitive aging are especially pronounced. Differences in cognitive aging might be tied to the lack of or reduced access to medical care and, as a result, suffer disproportionately from negative health outcomes. As the global population grows, diversifies, and grays, there is an increasing need to understand these inequities.

Race

African Americans

thumb|Life expectancy in the US by race

thumb|Life expectancy in the US by race and sex, with calculated sex gap

thumb|Probability of dying at various ages in the US in 2019 by race and sex Healthy cardiovascular function is critical for maintaining neurocognitive efficiency into old age. [[Attention, verbal learning, and cognitive set ability are related to diastolic blood pressure, triglyceride levels, and HDL cholesterol levels, respectively.

Latinos

In the US, the Latino demographic is most likely to develop metabolic syndrome - the combination of high blood pressure, high blood sugar, elevated triglyceride levels, and abdominal obesity - which not only increases the risk of cardiac events and type 2 diabetes but also is associated with lower neurocognitive function during midlife. This takes place even though life expectancy for Latinos in the US is higher than for white and black.

Among different Latin heritages, frequency of the dementia-predisposing ε4 allele of apoE4 gene was highest for Caribbean Latinos (Cubans, Dominicans, Puerto Ricans, 12.6–17.5 %) and lowest among mainland Latinos (Mexicans, Central Americans, and South Americans, 11.0–11.2 %). At the same time, frequency of the neuroprotective ε2 allele was also highest for Caribbean Latinos (5.2–8.6 %) and lowest for those of mainland heritage (2.9–3.9 %). Among mainland Latinos, the most prevalent is the "median" ε3 allele: 85.2–86.2 % compared to 73.9–81.5% among Caribbean Latinos.

Indigenous Peoples

Indigenous populations are often understudied in research. Reviews of current literature studying natives in Australia, Brazil, Canada, and the United States from participants aged 45 to 94 years old reveal varied prevalence rates for cognitive impairment not related to dementia, from 4.4% to 17.7%. These results can be interpreted in the context of culturally biased neurocognitive tests, preexisting health conditions, poor access to healthcare, lower educational attainment, and/or old age.

Sex

Compared to their male counterparts, women's scores on the mini–mental state examination (MMSE) tend to decline at slightly faster rates with age. Males with mild cognitive impairment tend to show more microstructural damage than females with MCI, but seem to have a greater cognitive reserve due to larger absolute brain size and neuronal density. As a result, women tend to manifest symptoms of cognitive decline at lower thresholds than men do. This effect seems to be moderated by educational attainment - higher education is associated with later diagnosis of mild cognitive impairment as neuropathological load increases. Currently there are no known studies to identify a characteristic pattern of cognitive decline with age in transgender people.

Socioeconomic factors

Socioeconomic status is the interaction between social and economic factors. It has been demonstrated that socio-demographic factors can be used to predict cognitive profiles within older individuals to some extent. This may be because families of higher socioeconomic status (SES) are equipped to provide their children with resources early on to facilitate cognitive development. For children in families of low SES, relatively small changes in parental income were associated with large changes in brain surface area; these losses were seen in areas associated with language, reading, executive functions, and spatial skills. Meanwhile, for children in families of high SES, small changes in parental income were associated with small changes in surface area within these regions. With respect to global cortical thickness, low SES children showed a curvilinear decrease in thickness with age while those of high SES demonstrated a steeper linear decline, suggesting that synaptic pruning is more efficient in the latter group. This trend was especially evident in the left fusiform and left superior temporal gyri - critical language and literacy supporting areas.

A study showed that 50+ aged users of the dietary program SNAP "had about 2 fewer years of cognitive aging over a 10-year period compared with non-users" despite it having nearly no conditions for the sustainability and healthiness of the food products purchased with the coupons (or coupon-credits).

Notes

<blockquote>1. usually spelled ageing brain in British English</blockquote>

References

External links

National Institute on Aging: Instruments to Detect Cognitive Impairment in Older Adults.