Disease biomarkers and aging biomarkers may be the same?

Chronic age-related diseases. Age-related changes in the
proteome have been described and were found to be highly similar
to changes associated with chronic diseases. We give several
examples on the successful application of proteomics in the diagnosis,
prognosis and therapy of these chronic diseases. Longstanding
diabetes is associated with a decline in renal function
and diabetic nephropathy has become the most prevalent cause of
end-stage renal disease. Patients with type 2 diabetes particularly
progress to severe life-threatening coronary artery disease,
the leading cause of morbidity and mortality worldwide. Cancer
can be considered a chronic disease predominately observed
in the second half of life. Taken together, urological tumors of the
prostate and the bladder are the most incident malignancies
in the United States followed by breast cancer, and cause more
than 35% of incidences. Essentially, all clinical proteomic investigations
indicate that the approach to combine several disease-associated
markers to a clearly distinct panel appears to be well suited
for disease diagnosis, staging, progression, and for assessment
of prognosis of these chronic diseases.

Gerontology. 2009;55(2):123-37. Epub 2009 Jan 9.
Proteomics in gerontology: current applications and future aspects--a mini-review.

Schiffer E, Mischak H, Zimmerli LU.

Mosaiques Diagnostics and Therapeutics AG, Hannover, Germany. schiffer@mosaiques-diagnostics.com

Biomarkers of Aging and Disease: Introduction and Definitions.

The concept of biomarkers of aging and age-related disease began to appear in the gerontologic and geriatric literature in the early 1980s as investigators were wrestling with the disconnect between chronological age and lifespan across and within species. In those early days, the interest was in eliminating the confounding influence of disease from research on aging so that biomarkers of underlying processes of aging could be developed (Ludwig & Smoke, 1981; Reff & Schneider, 1982; Sprott & Schneider, 1985). The question of what was aging and what was disease was at the core of the development of scientific legitimacy for the young science of aging. A key question then (and in some places now) was whether aging and disease were separate entities or aging was simply the end result (sum of damage) of a lifetime of disease. Adherents of the "aging is disease" view held that biomarkers of aging, separate from disease were not possible. Adherents of the "aging is the result of basic underlying processes" argued that aging research needed to be conducted with disease free subjects (human and lower animal) in order to be valid. Biomarkers of aging would then be markers of the progress of these underlying processes.

Exp Gerontol. 2009 Jul 31
Biomarkers of Aging and Disease: Introduction and Definitions.
Sprott RL

Cortisol awakening rise in middle-aged women in relation to psychological stress.

The cortisol awakening rise (CAR) is defined as cortisol secretory activity in the first 45-60min immediately post-awakening. It has been suggested that psychological factors may disrupt the normal awakening rise. Recent research has shown that psychological stress may influence the magnitude of the CAR, however the findings have been mixed. This study examined the impact of stress on the CAR and the diurnal mean in a sample of middle-aged women.
The results suggest that psychological stress may be associated with a smaller cortisol awakening rise, a lower diurnal mean, poor lifestyle choices and high levels of psychological distress. These findings may have broader implications for future health risk and for an individual's ability to cope with imminent daily stressors and demands.

Psychoneuroendocrinology. 2009 Jun 9.
O'Connor DB, Hendrickx H, Dadd T, Elliman TD, Willis TA, Talbot D, Mayes AE, Thethi K, Powell J, Dye L.

Cancer and Senescence

Very interesting article in the March issue of Cancer Research Journal:

Senescence is an irreversible arrest triggered by stresses such as telomere shortening, DNA damage, or oncogenic signaling. Oncogene-induced senescence occurs in preneoplastic lesions, but it is absent from full-blown malignancies suggesting a tumor suppressor function. We recently found that depletion of the receptor CXCR2 [which binds to chemokines such as interleukin (IL)-8 or GROalpha] delays both replicative senescence and impairs the senescence response to oncogenic signals. Our findings suggest that signaling by IL-8 and GROalpha might limit tumor growth by reinforcing senescence early in tumorigenesis. The challenge remains in how to integrate this with the well-known tumor promoting effects of IL-8 and GROalpha.

A role for CXCR2 in senescence, but what about in cancer?
Acosta JC, Gil J.
Cancer Res. 2009 Mar 15;69(6):2167-70. Epub 2009 Mar 10.

Cathepsin d and eukaryotic translation elongation factor 1 as promising markers of cellular senescence.

Induction of premature senescence may be a promising strategy for cancer treatment. However, biomarkers for senescent cancer cells are lacking. To identify such biomarkers, we performed comparative proteomic analysis of MCF7 human breast cancer cells undergoing cellular senescence in response to ionizing radiation (IR). IR-induced senescence was associated with up-regulation of cathepsin D (CD) and down-regulation of eukaryotic translation elongation factor 1beta2 (eEF1B2), as confirmed by Western blot. The other elongation factor, eukaryotic translation elongation factor 1alpha1 (eEF1A1), was also down-regulated. IR-induced senescence was associated with similar changes of CD and eEF1 (eEF1A1 and eEF1B2) levels in the HCT116 colon cancer cell line and the H460 lung cancer cell line. Up-regulation of CD and down-regulation of eEF1 seemed to be specific to senescence, as they were observed during cellular senescence induced by hydrogen peroxide or anticancer drugs (camptothecin, etoposide, or 50 ng doxorubicin) but not during apoptosis induced by Taxol or 10 microg doxorubicin or autophagy induced by tamoxifen. The same alterations in CD and eEF1A1 levels were observed during replicative senescence and Ras oncogene-induced senescence. Transient cell cycle arrest did not alter levels of eEF1 or CD. Chemical inhibition of CD (pepstatin A) and small interfering RNA-mediated knockdown of CD and eEF1 revealed that these factors participate in cell proliferation. Finally, the senescence-associated alteration in CD and eEF1 levels observed in cell lines was also observed in IR-exposed xenografted tumors. These findings show that CD and eEF1 are promising markers for the detection of cellular senescence induced by a variety of treatments.

Byun HO, Han NK, Lee HJ, Kim KB, Ko YG, Yoon G, Lee YS, Hong SI, Lee JS.
Cancer Res. 2009 Jun 1;69(11):4638-47.

Expression of p16(INK4a) in peripheral blood T-cells is a biomarker of human aging.

Summary Expression of the p16(INK4a) tumor suppressor sharply increases with age in most mammalian tissues, and contributes to an age-induced functional decline of certain self-renewing compartments. These observations have suggested that p16(INK4a) expression could be a biomarker of mammalian aging. To translate this notion to human use, we determined p16(INK4a) expression in cellular fractions of human whole blood, and found highest expression in peripheral blood T-lymphocytes (PBTL). We then measured INK4/ARF transcript expression in PBTL from two independent cohorts of healthy humans (170 donors total), and analyzed their relationship with donor characteristics. Expression of p16(INK4a), but not other INK4/ARF transcripts, appeared to exponentially increase with donor chronologic age. Importantly, p16(INK4a) expression did not independently correlate with gender or body-mass index, but was significantly associated with tobacco use and physical inactivity. In addition, p16(INK4a) expression was associated with plasma interleukin-6 concentration, a marker of human frailty. These data suggest that p16(INK4a) expression in PBTL is an easily measured, peripheral blood biomarker of molecular age.

Role of visceral adipose tissue in aging.

Visceral fat (VF) accretion is a hallmark of aging in humans. Epidemiologic studies have implicated abdominal obesity as a major risk factor for insulin resistance, type 2 diabetes, cardiovascular disease, stroke, metabolic syndrome and death. Utilizing novel rodent models of visceral obesity, studies have demonstrated a causal relationship between VF and age-related diseases. In contrast, surgically removing large quantities of subcutaneous (SC) abdominal fat does not consistently improve metabolic parameters in humans or rodents, suggesting that SC fat accrual is not an important contributor to metabolic decline. There is also compelling evidence in humans that abdominal obesity is a stronger risk factor for mortality risk than general obesity. Likewise, we have shown that surgical removal of VF improves mean and maximum lifespan in rats, providing the first causal evidence that VF depletion may be an important underlying cause of improved lifespan with CR. Given the hazards of VF accumulation on health, treatment strategies aimed at selectively depleting VF should be considered as a viable tool to effectively reduce disease risk in humans. In summary, this review provides both corollary and causal evidence for the importance of accounting for body fat distribution, and specifically VF, when assessing disease and mortality risk.

Huffman DM, Barzilai N.
Biochim Biophys Acta. 2009 Jan 30.

reduced dehydroepiandrosterone sulfate (DHEAS) levels - biomarker of aging in male

Aging in male primates: reproductive decline, effects of calorie restriction and future research potential.

Although less dramatic than in females, male mammals experience decreasing reproductive function during aging. In primates, multiple facets of the hypothalamic-pituitary-gonadal axis show evidence of gradual age-related decline, including behavioral, neuroendocrine and endocrine alterations such as decreased testosterone levels, reduced circulating dehydroepiandrosterone sulfate (DHEAS) levels, increased numbers of sperm abnormalities, and a general decline in physiological responses. In this review we consider a range of age-related changes in males. These measures, including more subtle aging characteristics, are interesting additional indices for detecting the timing of age-related changes in behavioral, neuroendocrine, and endocrine responses. Evidence of potential effects of calorie restriction as an intervention in reproductive aging is also discussed. A discernable decline occurs in both metabolic and reproductive endocrine processes during male aging. This cascade of events includes neuroendocrine and behavioral changes; biomarkers such as circulating DHEAS also show clear age-related decline. The varied changes that occur during male aging are considered in the context of primate aging in general.

Age (Dordr). 2008 Sep;30(2-3):157-68. Epub 2008 Jul 9.

Sitzmann BD, Urbanski HF, Ottinger MA.

Biomarkers of aging are physical properties in the human body which indicate that the body is aging. It is indicators of the normal phenomena of growing old. They are not, however, simply things which change with age. In order to be called a biomarker, a factor has to satisfy a number of criteria. The best markers will be the ones which are not susceptible to influence from the outside environment. For example, in the US cholesterol levels increase with age, but this is due to the nature of the American diet and is not characteristic for other parts of the world. Thus, a true biomarker would satisfy the following criteria:
A. The marker must predict the rate of aging and be a better predictor of life span than chronological age.
B. It must be able to be tested on a regular basis
C. It must work both for humans and other species, such as laboratory animals
D. There is support from human clinical assessment and complementary research studies.
E. The studies are based on a significant representative sample.
F. The result is a clear association with aging.
G. A relatively narrow standard deviation is present.
So far, around 24 factors have met the criteria and can be considered biomarkers. They may be indicated especially for males or for females, and figures may vary between the sexes. Here is their list:

1. 17-ketosteroid/ 17-hydroxycortiosteroid ratio (male) 13. Handgrip strength
2. Ascorbic acid 14. Hemoglobin A1C
3. Basal Metabolic Rate 15. Lung capacity- FEV1
4. Blood pressure- pulse 16. Lung capacity- FVC
5. Blood pressure- systolic 17. Maximum oxygen update (male)
6. Body Mass Index (female) 18. Near vision
7. Caries index 19. Noradrenaline- plasma (male)
8. Creatinine clearance 20. Peridontal index
9. DHEA-S 21. PSA total (male)
10. Fibrinogen 22. Skin elasticity
11. Hair baldness (male) 23. Testosterone free (male)
12. Hair grayness 24. Zinc- serum

In addition, there are also a number of other factors which may be considered partially biomarkers of aging. The main problem with these is that their reliability has not been confirmed through a sufficient amount of clinical and experimental data. These include body flexibility, blood urea nitrogen, LDL cholesterol, melatonin levels, static balance, serotonin levels and many others. They are to a certain degree indicative of a person’s biological age, but should not be confused with other general health factors, which do not have a clear association with age.
Biomarkers of aging could be divided in three major categories. There are the ones which determine the biological age, e.g. skin elasticity and visual accommodation. There are markers which predict the remaining life expectancy; they include DHEA-S, hand grip strength, etc. Finally, there are factors which determine disease susceptibility, such as systolic blood pressure and glucose-tolerance tests. All of the biomarker tests can be classified either as laboratory tests (e.g. blood and urine tests) or as physical tests undertaken in a clinic.

from: J Steroid Biochem Mol Biol. 2003 Jun;85(2-5):329-35.