Nutritional disorders related to reduced protein intake have a prominent role among the factors that compromise the clinical condition of elderly patients, leading to a protein malnourished (PM) state [1], [2], [3]. The most common age-related causes of reduced protein intake are associated with inadequate diets whether due to loss of appetite, gastrointestinal issues, changes in food preference, financial condition, or other factors [1,3]. In this context, for the last years, hunger, food insecurity, and malnutrition became more evident as a consequence of inequality, especially among the elderly [4].

Aging is also known to be represented as a gradual loss of function across different tissues and the number of elderly individuals is steadily increasing as scientific knowledge advances [1,5]. Thus, the association of reduced protein intake and aging represents two facets of one larger issue: the decline in quality of life by the impairment of tissular function, with the hematopoietic system being one well documented example of degrading functionality resulting from these stimuli [6], [7], [8].

The hematopoietic system primarily encompasses the bone marrow (BM), where blood production occurs. This process, named hematopoiesis, is heavily dependent on a tightly regulated network of cellular interactions between the hematopoietic stem cell (HSC) and its surrounding environment composed of both hematopoietic and non-hematopoietic cell populations [9]. As a result of this complexity and high cell renewal rate, the BM is affected by protein deficits and aging, with both cases showing alterations that reverberate in the peripheral blood [8,10].

One important component of the regulatory BM microenvironment is formed by another population of multipotent cells dubbed mesenchymal stem/stromal cells (MSCs). MSCs were found to be a heterogeneous population residing in different BM niches destinated to closely interact with HSCs to support their growth and differentiation, and therefore also sustain hematopoiesis [9,11].

Similar to PM, aging shares the potential to alter the structure of the BM and it has been recognized to also cause cell-intrinsic changes among the BM's constituents [8,9]. Our group has recently described how aging and deficient protein intake influences BM MSCs in their immunoregulatory capacity, leading to changes in MSC functionality [2]; however, the impact of these cells on the physiology of the hematopoietic system as well as the consequences to surge hematopoietic malignant diseases in an elderly-protein deficient intake model is poorly understood.

Thus, considering how the hematopoietic tissue is heavily dependent on the integrity of its complex microenvironment's interactions [9,11], here we describe how aging in a model of PM can influence the regulation of hematopoiesis through the impairment of MSC function and integrity.