These are synaptic mitochondria, a fundamental structure for neuronal activity because they are located in areas of neuronal communication or synapses, which play an important role in the functionality of the hippocampus, a brain region that mediates learning and memory processes.

Her laboratory has investigated in experimental models aspects related to alterations in synaptic mitochondria that could contribute to compromised neuronal communication in aging, and the role of a molecule called curcumin in preserving their functionality.

A review article published by the scientific journal Ageing Research Reviews presented the findings obtained by Chilean researcher Dr. Cheril Tapia—from the Centro Basal Ciencia & Vida, of the Universidad San Sebastián—during the last six years. One of them addresses the antioxidant potential of turmeric to attenuate cognitive decline during aging.

These studies focus on the role of synaptic mitochondria, a cellular organelle essential for brain cell communication as they are located in the synaptic regions of neurons, where they provide energy, regulate calcium fluctuations following changes in synaptic activity, and serve as cellular signaling agents, in addition to playing a key role in memory decline during aging, which opens the door to potential therapeutic targets.

Among the findings of this laboratory, a study published in the International Journal of Molecular Sciences in 2023 stands out, which revealed that during the aging process, damaged mitochondria accumulate in the hippocampus. These mitochondria cannot produce energy efficiently, generate a large amount of species that cause oxidative damage, and are unable to properly handle an increase in calcium levels, which could contribute to the decline that occurs in aging.

However, the scenario is more complex since neurons, due to a particular asymmetric morphology, present at least two populations of mitochondria: synaptic ones, located at the synapse; and non-synaptic ones, which are distributed throughout the body and other neuronal compartments.

Another finding of interest is that synaptic mitochondria are more vulnerable to damage and fail earlier than non-synaptic mitochondria in the hippocampus of aged models, increasing the production of reactive oxygen species that generate oxidative damage at the synapse, providing less energy for synaptic processes, and inefficiently managing calcium variations following neuronal communication; alterations that are directly associated with the degree of cognitive decline manifested by the individual.

The potential of turmeric

In this context, a molecule called curcumin, which is widely consumed as an antioxidant and is present in the Indian-origin additive turmeric, promotes an improvement in the function of mitochondria located at neuronal contact sites, with a positive impact on memory in the tested models.

The publication in the journal Ageing Research Reviews summarizes this and other milestones of the team led by the national academic, which is one of the few in the world pursuing this line of work focused on synaptic mitochondria. Dr. Tapia's goal is to study the structural and functional differences between synaptic and non-synaptic mitochondria, as well as the factors that could make synaptic mitochondria more sensitive.

“Synaptic mitochondria play a fundamental role in maintaining neuronal function. Their proper functioning is essential for what we know as synaptic plasticity, which is necessary for neurons to transmit messages and sustain high neuronal activity over time, generating various cognitive processes,” the researcher points out.

Synaptic plasticity is an important concept in this dynamic, as it explains the ability of the nervous system to adapt its structure and functioning throughout life. This process occurs when the number or intensity of synaptic connections changes, and is fundamental for learning and memory. It occurs through long-term potentiation, which is the main mechanism of plasticity and enables memory generation.

In addition to generating energy, mitochondria manufacture molecules that act as cellular signals, although some, such as reactive oxygen species, can be harmful. “With aging, most mitochondrial processes are compromised, leading to synaptic mitochondria being more vulnerable, more damaged, and having lower turnover,” the scientist explained.

“This review article summarizes the work we have been doing for six years in this line of research, in addition to integrating the team's most recent publications. We have reviewed all the literature on this topic, discussing how mitochondria are transported to the synaptic region and what the elimination or turnover process is like when they are damaged,” Dr. Tapia pointed out.

New therapeutic targets?

Aging is a multifactorial biological process characterized by the progressive accumulation of molecular and cellular damage. In the brain, the hippocampus undergoes functional decline with age, caused by cellular deficits, decreased synaptic communication, and neuronal death, ultimately leading to memory impairment.

According to the report, one of the factors contributing to this dysfunction is mitochondrial failure, which could eventually make this organelle an attractive therapeutic target to prevent or reverse aging-related conditions, even in non-pathological contexts. In this scenario, preserving the functionality of synaptic mitochondria seems to be crucial.

In a study published in 2020, the team led by Dr. Tapia demonstrated how mitochondrial failures contribute to cognitive decline in aged models. The following year, they advanced the understanding of synaptic mitochondrial failure, identifying the presence of an abnormal protein inside this organelle, which could be key to its vulnerability.

“When we talk about the vulnerability of synaptic mitochondria, this is supported by the fact that, when challenged with certain stimuli, which can be stressful or harmful, these mitochondria tend to quickly lose their function instead of responding positively,” notes the academic from the Universidad San Sebastián, who highlights the potential of this organelle to become a therapeutic target during aging.

The team also explored potential therapeutic approaches, including antioxidants. In the same 2020 article, Dr. Tapia and her team investigated the capacity of a “potent antioxidant with a potential impact on mitochondria,” as this molecule considerably improves their functions. It is called curcumin and is an extract of turmeric, an additive of Indian origin that comes from a perennial plant of the ginger family. The researcher emphasizes that, by improving mitochondrial function, an optimization of memory-associated processes is consequently observed.

“A projection of this work, and where we want to aim, is that if we maintain the functionality of synaptic mitochondria, there could be less memory decline,” points out the researcher from the Centro Basal Ciencia & Vida of the USS, who highlights that the studies have contributed to thoroughly describing alterations and functions affected by deficiencies in these neuronal structures.

Recent studies have also suggested that overloading mitochondrial function can aggravate or exacerbate its decline. This is even more critical due to the high neuronal activity to which they are exposed, so reducing their workload within healthy margins could be beneficial.

“It is a surprising finding that partially inhibiting mitochondrial function reduces alterations, for example, associated with the development of Alzheimer's disease. In analogy with a household appliance, if we limit its use to 80% of its capacity, we could prolong its lifespan and thus maintain greater neuronal function for longer,” the academic suggests.

Preserving mitochondrial health

The group of researchers also highlights the social relevance of their studies: improving the understanding of the causes of aging will be fundamental in designing more effective public policies and preventive health strategies over the coming decades.

“It is important that we make visible that cognitive decline exists in elderly individuals and is not only related to pathological conditions, as it can occur even in the absence of dementia. There is a high number of people who do not suffer from neurodegenerative diseases, such as Parkinson's or Alzheimer's, and begin to lose their memory, reaching a scenario of mild or moderate cognitive decline. It is relevant to take this into account, and we want to bring this to the table, that there are other ways to prevent or attenuate these alterations, for example, by preserving proper mitochondrial functioning,” the national scientist underscores.

Globally, average life expectancy rose from 66.5 years in 2000 to 72 in 2016 (74.2 years for women and 69.8 for men), according to the World Health Organization (WHO). The entity has warned of the need to pay greater attention to gender differences in the formulation of health policies. In Chile, the figure is around 80 years, and the female population reaches 85 years (five more than the male population).

But the projections are even more challenging: by the year 2050, older adults will represent nearly a third of the national population, and women could live up to 87 years (and men up to 84). As a reference, in 1992, people over 60 years of age made up only 9.5 percent of our country's inhabitants.

“This demographic shift highlights the urgent need for preventive strategies and policies that promote healthy aging, considering gender differences in the impact of aging and the opportunities to mitigate its effects,” concluded Dr. Cheril Tapia.

Text by Luis Francisco Sandoval. Agencia Inés Llambías Comunicaciones.