Aging is an inevitable facet of life, and yet the biology underlying this actuality remains poorly understood.
Even though it affects every organ in the body, ageing cannot be explained by a single pathway, and it is unclear what exactly causes the considerable changes in the brain.
Since declining mortality rates have boosted life expectancy—which grew by 6 years between 2000 and 2019 from 66.8 to 73.4 years—the causes and mechanisms of ageing have grown in importance. As a result, age-related sickness is now substantially more prevalent.
Given that all people endure physiological and cognitive changes as they age, it can be difficult to distinguish between abnormal and normal ageing. But it is still unclear what genetic, biochemical, and environmental variables push these changes past the point at which they become neurodegenerative.
The brain begins to lose volume after the age of 40 and does so at an increased rate until the age of 70.
Reduced total volume is caused by cerebral atrophy, which is also responsible for increased ventricular volume. Unknown mechanisms may be involved in this cell death. It is debatable whether a decrease in synapse number and a loss in cell volume together have a greater impact than a decrease in cell number alone. Injury, infection, or neurological diseases can speed up this process, while some studies have found that sex can slow it down.
Adulthood also sees a fall in the amount of grey matter, which is primarily made up of neuronal cell bodies. Despite reaching its peak at midlife, white matter volume (myelinated axons) also starts to decline after that. MRI can be used to detect abnormal myelination that shows up as white matter lesions (WML), which is another characteristic of ageing. They are highly correlated with various neurological diseases, including Alzheimer’s disease (AD), dementia, and Parkinson’s, and they reflect small vessel dysfunction.
Recent research employing MRI imaging and machine learning have been successful in predicting age with a mean absolute error of 5 years because structural changes in the brain’s architecture correlate so strongly with chronological age. This suggests a possible application of neuroimaging to recognise structural changes as a biological indicator of ageing and may be used to recognise “accelerated” or neurodegenerative variants.
Ageing, an inherent loss in cellular, tissue, and organismal function that also contributes to physiological deficiencies, is present together with chronological ageing. This decline entails defective mitochondrial activity, protein degradation, and oxidative stress responses and shows an imbalance between molecular damage and repair. As a result of metabolic changes in the brain, including as mitochondrial fragmentation, decreased electron transport, and increased oxidative DNA damage to the mitochondria, energy products like NAD+ and the harmful effects of reactive oxygen species eventually decline. Additionally, there is proof of diminished antioxidant activity and compromised oxidatively damaged molecular clearance.
Due to decreased clearance by the mitochondrial, antioxidant, and glymphatic systems, these senescent pathways cause a buildup of waste products and neurotoxic proteins. Protein accumulation is a hallmark of AD, which is characterised by amyloid beta plaques and neurofibrillary tangles and has an adverse effect on synaptic transmission. Genetic markers for ageing include the accumulation of unrepaired DNA damage and the ensuing loss of genomic integrity, which increases mistakes in the synthesis of RNA and protein molecules.
Since neurons remain permanently postmitotic and unable to execute double-stranded break repair, age-related DNA damage has significant impacts on the brain. Instead of fixing the complete genome by homologous recombination, neuronal cells concentrate on repairing genes that are being transcribed. It is currently unknown if certain DNA damage patterns may contribute to age-related diseases or whether the buildup of damaged DNA simply develops over time and serves as a gauge of advancing age.
Aging-related changes to the brain’s anatomical and chemical makeup have an impact on behaviour.
Memory is the cognitive capacity that ages most uniformly. Working memory, attention, and executive function tasks have all shown age-related differences. It is believed that the slower processing speed and increased sensitivity to distraction while doing a task are to blame for these “non-pathological” cognitive alterations. It has proven difficult to comprehend the mechanisms that determine whether elderly people do better or worse.
Brain atrophy may be a mechanism that fuels neurodegenerative illnesses’ pathological cognitive impairment. Volume decrease in specific areas, including the entorhinal cortex and hippocampal nucleus, has been linked to moderate cognitive impairment (MCI), according to a meta-analysis. In addition, additional research has found variations in hippocampus shrinkage rates in MCI patients who concurrently advanced to an AD diagnosis. Given the critical role these brain regions play in memory, it is not unexpected that illnesses characterised by memory loss are linked to them.
Although chronological ageing is a universal phenomenon, biological ageing exhibits individual variances, and it may be able to postpone the normal ageing processes in order to better protect the brain. Exercise, energy restriction, and antioxidant supplements are a few lifestyle adjustments that may be protective against age-related cognitive impairments.
Contrary to popular belief, however, moderate alcohol usage (1-6 drinks per week) has been linked to a lower incidence of dementia compared to abstinence, suggesting that delaying ageing may be more difficult than undoing age-related damage.
Parvathy Sukumaran 
