As people age, brain functions inevitably deteriorate, manifesting as symptoms such as memory loss, slow thinking, and difficulty concentrating. Among these, the threat of neurodegenerative diseases like Alzheimer's is especially prominent and has become one of the most concerning health issues for the elderly. Brain aging is a complex physiological process involving both structural and functional decline.
The Impact of Aging on the Brain
A comprehensive analysis of 56 MRI studies, collecting data from 2,211 healthy individuals from childhood to old age, revealed the dynamic changes in brain volume throughout life.[1]
- During childhood and adolescence, brain volume increases, peaking at around 9 years old with a 1% annual growth rate, then slows down, and starts to decline gradually at 13.
- From 18 to 35 years old, brain volume may increase or remain stable without significant tissue loss.
- After 35 years old, brain volume begins to decrease at an annual rate of 0.2%, which accelerates to more than 0.5% per year by the age of 60.
- For elderly over 60, the annual rate of brain volume decrease exceeds 0.5%.
These findings indicate that brain volume changes continuously throughout life. As we age, the brain undergoes various structural changes, including cortical thinning, white matter degradation, gyri loss, and ventricle enlargement. These morphological changes are often associated with cognitive decline, such as memory loss, reduced motor performance, and behavioral changes. Additionally, neurodegenerative diseases like Alzheimer's exacerbate brain aging, leading to significant structural changes and further cognitive decline. [2-3]
Figure 1: Hallmarks of brain atrophy are white and gray matter volume loss, cortical thinning, sulcal widening, and ventricular enlargement. [2]
Causes and Mechanisms of Brain Aging
Consistent with overall aging, brain aging involves 12 hallmarks of aging, with multifactorial and multilevel biological mechanisms impacting brain function.[4]
Molecular Level: Mitochondrial Dysfunction and Calcium Homeostasis Imbalance Leading to Neuronal Apoptosis or Necrosis.
Figure 2: Hallmarks of Brain Aging[4]
Brain aging involves changes in the function of various biomolecules and organelles within cells, particularly mitochondrial dysfunction. As we age, brain metabolism slows down, leading to decreased energy metabolism efficiency and the accumulation of reactive oxygen species (ROS).[5] This not only affects the normal function of nerve cells but may also exacerbate the accumulation of harmful substances like misfolded proteins and wastes. These protein plaques and clusters interfere with cell function (such as the β-amyloid plaques and Tau protein tangles in Alzheimer's disease). When damage within nerve cells accumulates to a certain extent, programmed death mechanisms are triggered. However, excessive neuronal apoptosis is also a significant factor in brain function decline, as the reduction in neuron numbers directly impacts the brain's information processing capacity.
Furthermore, calcium ion (Ca2+) homeostasis imbalance profoundly affects brain function and may contribute to neurodegenerative changes. When imbalanced, excessive Ca2+ influx into neurons triggers excitotoxicity and neuronal damage. High intracellular Ca2+ concentrations can activate calpain, caspase, and lipase, leading to the degradation of proteins, membranes, and cytoskeletal components, disrupting cell structure. Additionally, Ca2+ overload can cause mitochondrial membrane potential abnormalities, triggering the opening of mitochondrial permeability transition pores, leading to mitochondrial swelling, outer membrane rupture, and the release of pro-apoptotic factors, ultimately resulting in neuronal apoptosis or necrosis. Ca2+ signaling dysregulation can also impair synaptic transmission, long-term potentiation (LTP), and long-term depression (LTD), which are critical for learning, memory, and synaptic plasticity. These factors collectively lead to cognitive deficits and the progression of various neurodegenerative diseases.[6]
Figure 3: Calcium homeostasis deregulations in neurodegenerative diseases. AD, PD, HD, and ALS affect cytosolic calcium levels by deregulating different homeostatic control mechanisms. NMDAR or AMPAR activities, calcium buffering proteins, and mitochondrial functions were found to be deregulated in the 4 neurodegenerative conditions. α-Synuclein and Aβ peptides, the building blocks of Lewy bodies in PD and of senile plaques in AD, respectively, can form calcium-permeable ion channels at the plasma membrane. Abnormal ER calcium efflux by a mechanism of oversensitization of InsP3R (in HD and FAD) and RyR (in FAD), or of inactivation of the ER pump SERCA (in FAD), was also observed.
Cellular Level: Neuronal Atrophy and Demyelination Disrupt Effective Communication Between Brain Regions
The aging brain exhibits neuronal atrophy, involving cell body shrinkage, dendritic retraction, and reduced synaptic connections. This structural degeneration affects neuronal connectivity and plasticity, leading to decreased efficiency in neural signal transmission and subsequent downregulation of neural network integration and processing capabilities.[7] Additionally, demyelination, or the degradation of the protective sheath around nerve fibers, slows down nerve impulse propagation, making neural signal transmission inaccurate, disrupting effective communication between brain regions, and is associated with white matter lesions, axonal degeneration, and cognitive decline. [8] [9]
Brain function depends on the number and quality of nerve cells. With aging, the number of nerve cells in the brain may decrease, and structural changes may occur. However, the brain has multiple compensatory mechanisms to offset this loss:[10]
a) Redundancy: The brain has redundant cells that can function normally, helping to compensate for nerve cell loss due to aging and disease. [11-12]
b) Formation of New Connections: As the number of neurons decreases, remaining neurons establish new connections to actively compensate for age-related neuronal loss. [13]
c) Generation of New Neurons: Certain parts of the brain can generate new nerve cells, especially after brain injury and stroke, including the hippocampus (associated with memory formation and retrieval) and basal ganglia (coordinating movement). [14-15]
d) Remyelination: Oligodendrocyte progenitor cells can promote remyelination of nerve fibers, countering demyelination caused by oligodendrocyte dysfunction and death.[16]
Although these mechanisms can partially mitigate the damage caused by brain function decline, with advancing age and disease progression, these functions will gradually be lost, and we must ultimately face the consequences of brain aging.
Tissue Level: Vascular Lesions and Increased Blood-Brain Barrier Permeability Leading to Damage to the Brain's Internal Environment
Like other organs in the body, brain function relies on the supply of oxygen and nutrients delivered through the systemic vascular system, which includes a complex network of blood vessels. This process showcases two notable features of the brain: extremely high metabolic demand and limited capacity to store nutrients, making it highly sensitive to supply interruptions. Therefore, the brain requires continuous blood supply. As we age, brain vascular density decreases, hardness and tortuosity increase, leading to reduced cerebral blood flow and prolonged arterial transit time, causing chronic hypoperfusion and ischemia. This chronic ischemia can lead to cognitive decline, manifesting as memory loss, slowed thinking, impaired executive function, and in severe cases, vascular cognitive impairment or dementia. [17-18]
The blood-brain barrier (BBB) is a crucial protective structure of the central nervous system, composed of brain microvascular endothelial cells, pericytes, and astrocyte end-feet. It controls the exchange of substances between the blood and the brain, ensuring the stability of the brain's microenvironment and the normal functioning of neural synapses. The BBB effectively prevents the entry of pathogens, toxins, and inflammatory cells while allowing the necessary nutrients, peptides, and proteins to enter the brain through specific transport mechanisms. It also actively clears harmful substances via mechanisms such as ABC transporters, maintaining the stability of the brain's internal environment.
However, when inflammation or infection damages the BBB, inflammatory cells and mediators may infiltrate brain tissue, triggering brain inflammation. This inflammatory response can lead to neuronal damage, brain edema, neurotransmitter imbalance, and other severe consequences, even life-threatening situations. Thus, the BBB's function is crucial for protecting brain health. As the "gatekeeper" of the nervous system, the BBB maintains the brain's internal microenvironment balance, prevents the intrusion of harmful substances, and ensures the supply of essential substances, providing a solid foundation for the brain's normal function.[19-21]
Figure 4: Vascular blood–brain barrier in health (upper panel) and during systemic inflammation (lower panel). The figure is divided into four vertical sections corresponding to the four types of BBB responses to increasing levels of systemic inflammation described in the text. In the first vertical section on the left, changes in signaling are exemplified by up- and downregulation of carriers and receptors. This is followed by increased cell and solute trafficking across the BBB, with enhanced transendothelial vesicular transport and tight junction breakdown, in the second and third vertical sections. A rolling lymphocyte has adhered to the endothelium, after which diapedesis into the potential perivascular space occurs, where the lymphocyte can crawl (step 1) or penetrate the glia limitans (step 2) to enter the brain parenchyma. The fourth vertical section illustrates structural damage to various components of the BBB, including the glycocalyx, basement membrane, endothelial cells, pericytes, and astrocytic endfeet [21]
Brain aging involves structural, molecular, cellular, and tissue-level changes, leading to cognitive decline. Structural alterations like cortical thinning and white matter degradation, along with mitochondrial dysfunction and calcium imbalance, result in neuronal apoptosis. Cellular changes such as neuronal atrophy and demyelination disrupt neural communication. At the tissue level, vascular lesions and blood-brain barrier permeability issues lead to chronic ischemia and inflammation. Despite compensatory mechanisms like neurogenesis and remyelination, aging ultimately prevails. Understanding these processes can guide interventions to preserve cognitive health, offering hope for healthier aging and improved quality of life for the elderly.
