New Insights Into Longevity: How Organ-Specific Metabolic Alterations Contribute to Aging

Despite all of the advances that longevity research has made in recent years, metabolic changes and dysfunction are an under-studied piece of the aging puzzle. Also known as metabolomics, this field of study looks at comprehensive changes to small compounds that contribute to or are byproducts of metabolism. Joining the ranks of genomics and proteomics, which study genes and proteins at large scales, metabolomics is the most recent “omics” to join the scene, assessing how these small molecules called metabolites change with aging and various disease states. 

Humans contain thousands of metabolites, with their roles ranging from protein and fat breakdown to immune responses to inflammation. However, the metabolome varies widely — both from person-to-person and from birth to old age. With increasing age, it’s known that some metabolites accumulate while others decline, but a comprehensive set of age-related metabolic biomarkers has yet to be identified.

In a recent study published in Biomolecules, a research team based out of Austria aimed to do just that — to uncover and compare a full metabolic signature between young and old mice. Zhang and colleagues pinpointed a robust set of tissue-specific metabolites that change with age, enabling the research team to fully capture the metabolic profiles of an older mouse. With these results, researchers are one step closer to elucidating the metabolic causes and potential treatments of age-related disorders in humans. 

Dysregulated Metabolites Drive Organ Damage and Dysfunction

There is increasing evidence that metabolic changes do not occur solely as a consequence of aging but, rather, that these metabolic shifts can drive the aging process itself. The risk of chronic diseases increases concurrently with age, with 80% of older adults afflicted with one or more chronic conditions. Although many of these diseases have wide variations in symptoms and manifestations, they share a commonality of dysregulated metabolic function in some capacity. 

In this study, Zhang and colleagues identified the metabolic changes occurring in six different organs: the brain, heart, kidneys, lungs, liver, and spleen. After comparing the metabolites in young and aged mice (translating to approximately 20 and 70 in human years, respectively), the research team gained new insights into the array of metabolites involved in the organ damage and dysfunction that is commonly seen with age.

Branching Out With New Biomarkers of Aging

One aspect of the aged mouse metabolome that jumped out at the researchers involved how they broke down or catabolized amino acids, the building blocks of proteins. Three of these building blocks — isoleucine, leucine, and valine, also known as branched-chain amino acids (BCAAs) — were found to be significantly altered with age. Despite their essentiality in the diet, previous research has found that elevated blood levels of BCAAs are linked to Alzheimer’s disease, type 2 diabetes, and cardiovascular disorders. 

It’s thought that this reduction in BCAA catabolism may impact aging by disrupting autophagy — our body’s way of recycling or removing damaged or toxic cells or cell parts — in neurons and cardiomyocytes (heart muscle cells). Decreased autophagic activity is considered a hallmark of aging and is implicated in many — if not all — chronic and age-related diseases. In this study, high levels of BCAA metabolites were found in the aged mouse brain, heart, and lungs, adding to the evidence that elevated BCAAs may be a promising biomarker for assessing aging and diseases related to these organs.

Locating the Longevity-Boosting Metabolites 

Several other metabolites involved with fighting inflammation and potentially extending lifespan were altered in the organs of aged mice. First, the aged kidneys showed much lower levels of succinate, a compound that plays a vital role in helping the mitochondria of our cells generate energy in the form of ATP. Succinate has also been found to activate specific genes related to longevity in other species, increasing resistance to stress and extending lifespan. Although low succinate levels have previously been implicated in other diseases, including high blood pressure and liver damage, this research suggests that succinate may play a more important role in aging than previously thought, especially in the kidneys. 

Next, the aged mouse liver and lungs exhibited low levels of two metabolites that fight inflammation — nicotinamide and inosine. Nicotinamide is a form of vitamin B3 that comprises part of NMN (nicotinamide mononucleotide). NMN is a precursor to NAD+, a critical coenzyme and bioenergetic molecule in all of our cells; low levels of NAD+ are implicated in aging and age-related diseases. Healthy levels of inosine, a compound that helps translate genetic codes into proteins, modulate both the immune and inflammatory responses. As aging and many chronic diseases are rooted in inflammation, low inosine levels could increase inflammatory pathways and further contribute to damage or disease in these organs.

Lastly, five out of the six organs (excluding the lungs) displayed low uridine levels, a nucleotide compound that makes up RNA molecules carrying instructions from DNA to synthesize proteins. The similarities of uridine levels between the various organs suggest that low levels of this metabolite may be used as a biomarker of both tissue-specific and whole-body aging. Previous research has found that adequate uridine levels are linked to reduced inflammation and improvements in neurological disorders. This may be because uridine reduces cellular senescence — when cells undergo irreversible cell cycle arrest, losing their function but remaining in the body. Senescent cells then secrete inflammatory compounds and cause damage to nearby tissues. Previous research has found that an increase in cellular senescence reduces the production of nucleotides like uridine, which could impair replication and repair of DNA and contribute significantly to aging.

The Future of Mastering the Metabolome 

By revealing these tissue-specific metabolic changes seen in aged mice, Zhang and colleagues identify several prominent biomarkers that future pharmaceutical interventions could target to prevent or slow down age-related diseases — or aging itself. Although still in its infancy compared to the other “omics,” the study of metabolomics is emerging as a powerful tool for understanding how and why our organs age. With this study as a starting point — and future research that depicts the metabolic signatures of aged humans in addition to animals — we may soon be able to determine and monitor the ages of each organ in the body and provide tissue-specific treatment to combat its decline and dysfunction with age. 

References: 

Delfarah A, Parrish S, Junge JA, et al. Inhibition of nucleotide synthesis promotes replicative senescence of human mammary epithelial cells. J Biol Chem. 2019;294(27):10564-10578. doi:10.1074/jbc.RA118.005806

Srivastava S. Emerging Insights into the Metabolic Alterations in Aging Using Metabolomics. Metabolites. 2019;9(12):301. Published 2019 Dec 13. doi:10.3390/metabo9120301

Tobias DK, Lawler PR, Harada PH, et al. Circulating Branched-Chain Amino Acids and Incident Cardiovascular Disease in a Prospective Cohort of US Women. Circ Genom Precis Med. 2018;11(4):e002157. doi:10.1161/CIRCGEN.118.002157

Tournissac M, Vandal M, Tremblay C, et al. Dietary intake of branched-chain amino acids in a mouse model of Alzheimer's disease: Effects on survival, behavior, and neuropathology. Alzheimer’s Dement (N Y). 2018;4:677-687. Published 2018 Dec 10. doi:10.1016/j.trci.2018.10.005

Zhang F, Kerbl-Knapp J, Akhmetshina A, et al. Tissue-Specific Landscape of Metabolic Dysregulation during Ageing. Biomolecules. 2021;11(2):235. Published 2021 Feb 7. doi:10.3390/biom11020235