FROM AGING TO AGELESS: THE REVOLUTIONARY APPROACH TO REVERSING BRAINAGE

Aging, as normal as it seems, is not just wrinkles and back aches. As we age, our organs start to degrade, especially the organs that contain postmitotic cells endure the most damage since the cells cannot differentiate anymore. One such organ is our brain. As we progress in age, we simultaneously regress in our cognitive abilities, memories, and orientation. The rate of this regress and it’s severity depends on every individual and their history of genetics. In most severe cases, this regress can cause neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and primary progressive multiple sclerosis.

Cognitive aging was mainly associated with the neuronal cells of the brain which are referred to as the ‘computational unit’. Although, researchers state that the impairment of non-neuronal cells can also add to cognitive aging since they perform various activities that cannot be neglected, such as, regulation of synapse formation and function by astrocytes, myelination and provision of trophic support to neurons by oligodendrocytes, protection of CNS against injury and disease, removal of weak neuronal synapses to establish precise patterns of neuronal connectivity in the brain.

Immune aging is one of the major effects observed during cognitive aging, which is majorly characterized by immune senescence, defective initiation and resolution of immune responses and inflammation in the brain. The lymphatic drainage system of inflammatory products produced by the brain is impeded with age. This impediment results in the accumulation of inflammatory products and increased production proinflammatory cytokines such as interleukin-6 (IL-6), Tumor necrosis factor alpha (TNFα), acute-phase proteins, reactive oxygen species (ROS), and autoantibodies. In addition to this, there is an accumulation of clonally expanded T cells which was observed in aged brain. When T cells in the brain become inflamed, they make it harder for new neurons to grow and change the way glial cells work. This makes the effects of brain aging worse.

A subset of T cells with potent anti-inflammatory and pro-repair functions are the regulatory T cells (Treg) found in both lymphoid and nonlymphoid organs. The Tregs have been found in low numbers in human and mouse brain. Scientists suggest that Tregs may be helpful in protecting against various brain diseases that involve inflammation or degeneration. To use Tregs as a treatment, researchers have proposed two methods: either delivering Tregs directly using cell-based techniques, or providing drugs that enhance Tregs, such as IL2 which is important for their survival. However, the outcomes of these methods have varied between different experiments and treatments.

The researchers at Leuven, Belgium have proposed a brain specific IL2 delivery system. After identifying the molecular markers of aging in the glial compartment of the brain using young and aged mice, they were able to differentiate the results of their treatment. There was a partial restoration of this signal which confirmed the efficiency of this treatment. The treatment enhanced the behavioral characteristics of the mice rather than the motor abilities. The treated mice showed improved spatial learning.

The article discusses a study that suggests an analog of PHP.GFAP-IL2 treatment could prevent cognitive decline during human aging. However, there are several barriers to translation, such as the degree to which the aging process is conserved across species and the kinetics involved in cognitive decline. It is not clear whether the treatment actively reverses the molecular, cellular, and behavioral processes of aging or just prevents the decline. Additionally, cognitive decline is driven by various factors, and response to an IL2-based therapy will vary from person to person. The delivery system used in the study performs poorly in nonhuman primates, but alternative AAV capsids are available that perform well in humans. Long-term safety data is essential for the development of longevity treatments. The study used interleukin2 and an AAV-based viral vector to treat aged mice and assess the effects on the brain and cognitive function. The treatment partially reversed the aging signature in glial cells and prevented age-related decline in spatial learning, with treated aged mice performing similarly to young mice in tests.

Mild cognitive decline is becoming a widespread problem globally, affecting about 40% of people over the age of 60. This condition can be distressing and worrisome, as one-third of individuals with mild cognitive decline eventually develop dementia within five years, which leads to a loss of independence. Gene delivery systems have the potential to provide long-term, targeted delivery of anti-inflammatory proteins to the brain. The findings of this study demonstrate the potential of using gene delivery of IL2 and expanding regulatory T cells to halt mild cognitive decline in aging individuals, providing a proof-of-concept for this approach.

References:

Molecular and cognitive signatures of ageing partially restored through synthetic delivery of IL2 to the brain (https://www.embopress.org/doi/full/10.15252/emmm.202216805)